Palifermin in Patients with Hematological Malignancies Undergoing Autologous Hematopoietic Stem Cell Transplantation (HSCT): The Italian Early Access Program (EAP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5236-5236
Author(s):  
Laura M. Cavagna ◽  
Gaetano Bonifacio ◽  
Emanuele Angelucci ◽  
Alessandro Fanni ◽  
Giuseppe Milone ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Adverse Events ◽  
Interim Analysis ◽  
Hematological Malignancies ◽  
Hematologic Malignancies ◽  
World Health ◽  
High Dose ◽  
Hematopoietic Stem ◽  
The Mean

Abstract Oral mucositis (OM) is an acute, severe and often dose-limiting toxicity in patients undergoing HSCT. OM significantly affects functional status and patients’ quality of life; however no effective therapy was available for this condition. Palifermin (Kepivance®) is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology. KGF binds to its receptor on epithelial cells, stimulating their proliferation, differentiation, and migration. Palifermin has been shown to decrease the incidence and duration of severe OM in patients with hematologic malignancies receiving myelotoxic therapy and HSCT. In Italy, compassionate use protocols are considered EAP and are regulated by a decree issued by the Ministry of Health (MoH) on May 8th 2003. The objective of the Decree is to ensure that patients have access to experimental therapies outside clinical trials, when no valid therapeutic alternative exists. Approval is granted in case of serious or rare diseases or life-threatening conditions. After Ethical Committee (EC) approval and notification to MoH, the drug can be supplied in response to an unsolicited request from a physician. The drug is then administered under the physician’s direct responsibility. During EAP, the Decree allows collection of the patient’s data similar to an observational trial. From July 2005 through July 2006 a total of 26 centers have requested the drug and obtained approval from local EC. Each center collected the following data on a case report form: vital signs, disease status and treatment, palifermin administration, mucositis, analgesic use, parenteral supplementation, common laboratory tests and duration of hospitalization. A total of 175 adults patients with hematological malignancies treated with autologous SCT participated in the EAP. In an interim analysis, data from 41 patients (24 men; 17 women; median age 52.44) were analyzed. The most common diagnoses were multiple myeloma (MM) (n=16) and non-Hodgkin lymphoma (NHL) (n=15). Conditioning therapy and supportive care were administered according to standard institutional practice (high-dose melphalan for MM and the BEAM regimen for NHL). Palifermin 60 mcg/kg/day was given intravenously on 3 consecutive days before the conditioning regimen and on 3 days starting on the day of stem cell infusion. OM was evaluated daily for 28 days after transplantation or until severe OM resolution using the five-grade World Health Organization (WHO) oral-toxicity scale. Safety was assessed on the basis of the incidence of adverse events. The incidence of severe OM (Grade 3–4) was 17% and the mean duration was 2.2 ± 3.5 days (CI, 1.1–3.3) in patients with OM Grade 0–4 while in patients with OM G3-4 the mean duration was 6.9 ± 2.5 (CI, 4.5–9.2). Adverse events (mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration) were mild to moderate in severity and were transient. The frequency of adverse events was consistent with those observed in clinical trials. In conclusion, the Italian EAP experience with palifermin suggested that results were consistent with those of pivotal studies in patients with hematologic malignancies undergoing HSCT. From the results of the interim analysis of the Italian EAP, the use of palifermin in this setting appears to be feasible and was widely accepted by participating physicians and patients.

A Randomized Trial of Two 2-Dose Influenza Vaccination Strategies for Patients Following Autologous Hematopoietic Stem Cell Transplantation

2020 ◽  
Author(s):  
Benjamin W Teh ◽  
Vivian K Y Leung ◽  
Francesca L Mordant ◽  
Sheena G Sullivan ◽  
Trish Joyce ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Influenza Vaccination ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Influenza B ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Background Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous hematopoietic stem cell transplantation (autoHCT) patients. Methods A randomized, single-blind, controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomized 1:1 to high-dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or 2 SD vaccines (SD-SD arm) 4 weeks apart. Hemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2, and 6 months post–first dose. Evaluable primary outcomes were seroprotection (HI titer ≥40) and seroconversion (4-fold titer increase) rates and secondary outcomes were geometric mean titers (GMTs), GMT ratios (GMRs), adverse events, influenza-like illness (ILI), and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion. Results Sixty-eight patients were enrolled (34/arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentages of patients achieving seroprotection were 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all P > .05), and 78.8% and 97.1% for influenza-B/Yamagata (P = .03), respectively. Seroconversion rates, GMTs and GMRs, and number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR, 4.3; 95% CI, 1.2–14.9; P = .02). Conclusions High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either 2-dose vaccine schedules. Clinical Trials Registration Australian New Zealand Clinical Trials Registry: ACTRN12619000617167.

Acute Enterocolitis Incidence in Patients with Hematological Malignancies Receiving Myelotoxic Therapy Requiring Hematopoietic Stem Cell Support - Palifermin Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5461-5461
Author(s):  
Isabel Sousa ◽  
Catarina Geraldes
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Adverse Events ◽  
Stem Cell Transplantation ◽  
Parenteral Nutrition ◽  
Hematopoietic Stem Cell ◽  
Oral Mucositis ◽  
Hematological Malignancies ◽  
Control Group ◽  
Hematopoietic Stem

Abstract Background: Chemotherapeutic agents can cause severe oral and gastrointestinal mucositis, for which there is currently no treatment. Previous research demonstrates that palifermin - keratinocyte growth factor - is potentially antimucotoxic, reducing the duration and severity of oral mucositis after intense chemotherapy in hematological cancers. The primary aim of this study was to determine palifermin effectiveness in ameliorating chemotherapy-induced diarrhoea and oral mucositis incidence. Palifermin adverse events were also assessed. Methods: Retrospective observational study involving patients with hematological malignancies undergoing autologous hematopoietic stem-cell transplantation after myelotoxic therapy. All the patients received antibiotic, antifungal, and antiviral prophylaxis. Patients being treated with palifermin to decrease the incidence and duration of severe oral mucositis (Palifermin Group) were compared to a control group of patients who did not receive palifermin (Control Group). Palifermin was administered during 3 consecutive days, before and after myelotoxic therapy in a 60 μg/Kg daily intravenous dose. Results: Twenty-four patients were included, 8 in Palifermin Group and 16 in Control Group. Baseline malignancies were Hodgkin and non Hodgkin lymphoma, acute myeloid leukemia, and multiple myeloma. All patients underwent autologous hematopoietic stem-cell transplantation after the following conditioning regimes: BEAM, BuCy, and Mel200 respectively. In Palifermin Group, 62.5% were male, mean age 47.6±13.0 years, mean disease duration of 22.3±10.1 months (N=8). In Control Group 56.3% were male, mean age 45.8±12.1 years (N=16). Mean performance status (Karnofsky Index) was 80±14.1% and 71.3±15.1%, in each group, respectively. No statistically significant differences between Palifermin and Control Groups were found regarding the degree of diarrhoea, although in the Palifermin Group the majority of patients presented a grade 2 (N=3) and in the Control Group a grade 3 (N=6). In the Palifermin Group there was a tendency for a lower incidence of hypoalbuminemia [12.5% (Palifermin Group) vs. 50% (Control Group)], which corresponded to a significant lower difference in the needs for receiving parenteral nutrition (P=0.011). Nevertheless, these findings were not translated in less febrile episodes or less iv antibiotic therapy days. There were no significant differences between the two groups regarding the degree of oral mucositis, the number of days of analgesic opioids use, and the number of hospitalization days, most probably due to the small sample considered. The most common adverse events in the Palifermin Group were reversible erythema and edema of the face and upper trunk that have occurred only in 3 patients. Weight increase was mild and similar in both groups of patients [Median weight increase±SD: 1,0±1,7 Kg (Palifermin Group) vs 2,0±2,5 Kg (Control group)]. Conclusion: Gastrointestinal and oral mucositis are common consequences of cancer therapy with a direct and significant impact on the quality of life and care costs, also affecting patient’s survival. Our exploratory study shows that palifermin treatment is well tolerated, potentially reducing diarrhoea and the incidence of hypoalbuminemia, and significantly reducing the needs for parenteral nutrition. However further studies with an increased number of patients will be necessary to provide more evidence concerning palifermin efficacy in the management of these cancer therapy’s debilitating side-effects.

High Dose Plerixafor Is Safe and Mobilizes Higher Numbers of CD34+ Cells Compared with Standard Dose Plerixafor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 585-585
Author(s):  
Jeremy M Pantin ◽  
Xin Tian ◽  
Matthew M. Hsieh ◽  
Lisa Cook ◽  
Theresa Donohue ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Adverse Events ◽  
Dose Level ◽  
Peripheral Blood ◽  
Standard Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Cd34 Cells

Abstract Abstract 585 Introduction Plerixafor is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXCR4. This results in therapid release of CD34+ cells into circulation, which can then be collected by apheresis. Plerixafor is FDA approved at the 240 μg/kg dose to be used in conjunction with G-CSF to mobilize autografts for transplantation. Allogeneic grafts can also be mobilized using single agent plerixafor without G-CSF, and following transplantation, result in sustained donor derived hematopoiesis. However, when the 240 μg/kg dose is used, 1/3 of donors fail to mobilize minimally acceptable doses of CD34+ cells. Recently, we demonstrated the safety of administration of a single dose of 480 μg/kg of subcutaneous (sc) plerixafor in humans. We subsequently conducted a randomized cross-over trial comparing CD34+ mobilization in healthy subjects mobilized with a single dose of sc plerixafor given at either a high dose (480 μg/kg) or a conventional dose (240 μg/kg). Methods Twenty normal healthy volunteers were randomized and received either a 240 or 480 μg/kg dose of sc plerixafor followed by at least a 2 week wash out period then were administered the other dose of plerixafor. Circulating numbers of leukocytes and CD34+ cells/μlwere measured at multiple time points for 24 hours following each plerixafor injection and the CD34+ AUC over 24 hours was calculated for each subject at each dose level. Peripheral blood colony forming unit (CFU) assays were performed at baseline and 6 hours after plerixafor dosing. Adverse events were graded using CTCAE version 3.A sample size of 20 subjects was determined to have over 90% power to detect an absolute CD34+ count difference of 10/μl using this crossover design and a two-sidedpaired t-test at the 0.05 level. Results Twenty-three subjects were enrolled and 20 completed administration of both doses. Peak circulating CD34+ cell numbers (median 31.5 vs 25, p=0.0009), circulating CD34+ cell numbers at 24hrs (median 15.5 vs 9, p<0.0001), and the CD34+ AUC over 24 hours (median 543 vs 411, p<0.0001) were all significantly higher following the administration of the 480 μg/kg plerixafor dose compared to the 240 μg/kg dose. The time to peak CD34+ was also slightly longer after the 480 μg/kg dose (median 10 vs 8 hrs, p=0.011). These differences were not related to the order of administration of the 2 different plerixafor doses. Although GM-CFUs from the peripheral blood at 6hrs following plerixafor were significantly higher compared to baseline levels at both plerixafordoses, there was no dose-effect relationship observed between drug dose and fold increase in GM-CFUs. The incidence and severity of AE's did not differ between lower and higher doses of plerixafor and no grade 3 or greater adverse events occurred at either dose level. Conclusion These preliminary data suggest high dose plerixafor can be administered safely and may mobilize more CD34+ cells than standard dose plerixafor. Furthermore, these data suggest mobilization following a single dose of plerixafor and a single apheresis procedure would result in graft collections containing higher CD34+ cell numbers when allogeneic stem cell donors are mobilized with high-dose plerixafor compared to standard-dose. Disclosures: Off Label Use: Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).

Phase 2 study of MGTA-145 + plerixafor for rapid and reliable hematopoietic stem cell (HSC) mobilization for autologous transplant in multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8023-8023
Author(s):  
Surbhi Sidana ◽  
Andriyana Bankova ◽  
Hitomi Hosoya ◽  
Lori S. Muffly ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Residual Disease ◽  
Hematologic Malignancies ◽  
Phase 2 ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Grade 3

8023 Background: MGTA-145 (GroβT), a CXCR2 agonist, has shown promising activity for HSC mobilization with plerixafor in pre-clinical models and healthy volunteers. Methods: This phase 2 single center study evaluates HSC mobilization with MGTA-145 + plerixafor and same day apheresis in patients with multiple myeloma. Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization was repeated for a second day if day 1 yield was < 6 x 106 CD34+ cells/kg. This interim analysis reports on mobilization in 10 patients (of 25 planned), including safety cohort of first 6 patients completing transplant. Primary endpoint is collection of 2 x 106 CD34+ cells/kg. Results: Median age was 63 years (range: 46-68), 50% were female, 22% had ISS stage 3 & 50% had high-risk FISH. Induction therapy was VRD in 7 and daratumumab + VRD in 3 patients; median induction duration: 4 months (3-6) & median lenalidomide exposure: 6 cycles (4-6), with > VGPR in 70%. Median total stem cell yield (CD34+ cells/kg x 106) was 7.1 (3-16.2), day 1 yield was 5.4 (1.1-16.2) & yield per apheresis session was 4 (1.1-16.2). 100% of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant (2 x 106 CD34+ cells/kg). Secondary endpoints of 4 and 6 x 106 CD34+ cells/kg in < 2 days were met in 90% & 80% patients. 30% patients underwent 1 apheresis, while 70% underwent 2 sessions. MGTA-145 was well tolerated. At least 1 adverse event (AE) was seen in 90% of patients, 20% had grade 2 AEs (anemia, hypokalemia) and 20% had grade 3 AEs (worsening of baseline grade 3 anemia; hypocalcemia); all resolved. Acute & transient bone pain was seen in 40% of patients (back-2, hip-1, sternum-1), all grade 1, all on day 1, & resolved without intervention after 6 minutes (3-10). All 6 patients in the safety cohort have completed transplant with melphalan 200 mg/m2. Median of 4.1 (3.4-5.6) x 106 CD34+ cells/kg were infused. All patients have engrafted timely (DiPersio Blood 2009); median time to neutrophil engraftment: 12 days (11-13) & platelet engraftment: 17 days (16-19). Apheresis graft analysis is available in these 6 patients. Grafts with MGTA-145+plerixafor showed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 31% of CD34+ cells, 27-52), higher than seen with G-CSF (6%, Goncalves TCT 2021). 67% of grafts were minimal residual disease negative with next generation flow cytometry. Conclusions: This is the first study to evaluate the novel regimen of MGTA-145 + plerixafor for same day stem cell mobilization & collection in myeloma/hematologic malignancies, with 100% efficacy in interim analysis and the first to demonstrate successful engraftment in patients with cells collected with this GCSF free regimen. Clinical trial information: NCT04552743.

STAT5 and STAT5 Inhibitors in Hematological Malignancies

2020 ◽  
Vol 19 (17) ◽  
pp. 2036-2046
Author(s):  
Manlio Tolomeo ◽  
Maria Meli ◽  
Stefania Grimaudo
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Myeloproliferative Disorders ◽  
Main Role ◽  
Cellular Functions ◽  
Hematopoietic Stem ◽  
Immunological Responses

The JAK-STAT pathway is an important physiologic regulator of different cellular functions including proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins, STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seems to be a key event in the pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review, we discuss the implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.

A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 615-615 ◽  
Author(s):  
Michael W. Schuster ◽  
J. Mehta ◽  
E.K. Waller ◽  
R.M. Rifkin ◽  
I. Micallef ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Oral Mucositis ◽  
Interim Analysis ◽  
Safety Information ◽  
Study Drug ◽  
Controlled Study ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Safety And Efficacy

Abstract Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.

Sign in / Sign up

Export Citation Format

Share Document