38 research outputs found
Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.
Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/
Anti-CD45 Pretargeted Radioimmunotherapy Prior to Bone Marrow Transplantation without Total Body Irradiation Facilitates Engraftment From Haploidentical Donors and Prolongs Survival in a Disseminated Murine Leukemia Model
s / Biol Blood Marrow Transplant 19 (2013) S211eS232 S228 chemotherapy was HIDAC (1-3 grams/m2 for 6-8 doses)/ Etoposide(15-40mg/kg) in 16 patients and growth factor alone in one patient. Median time from diagnosis to ASCT was 4.2 (range 3.6-7) months. Preparative regimen for ASCT was Busulfan (3.2mg/kg x 4)/Etoposide (60 mg/kg) in 12 patients and high dose melphalan in 5 patients. The median CD34 cells infused was 4.9 x 10e6/kg (range 2.8 to 15.9).All patients engrafted with a median time to neutrophil engraftment of 11 (range10-12) days. The median time to platelet engraftment was 20 (range15-40) days. The median length of inpatient stay during the ASCT admission was 14 (range 10-25) days. One patient died of progressive disease 14 months post ASCT. Two patients died in remission on day 53 (sepsis) and day 836 (unknown cause) post ASCT. Fourteen patients (82%) are currently alive in complete remission. at a median follow-up of 20 (range 140) months post ASCT. Conclusion: Consolidation of good risk AML patients with ASCT following induction of complete remission is safe and effective in preventing relapse in good risk AML patients
Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that down-modulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem
Androgen Receptor Overexpression in Mantle Cell Lymphoma: Potential Novel Therapeutic Implications
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Bendamustine (Treanda®), Etoposide and Dexamethasone (BED) Followed by GCSF Effectively Mobilizes Autologous Peripheral Blood Hematopoietic Stem Cells
Abstract 4126 Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for patients with advanced or treatment refractory multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Stem cell proliferation and mobilization can be enhanced though the addition of myelosuppressive chemotherapy to GCSF administration. Chemotherapeutic agents without cross resistance to prior therapies may support peripheral blood stem cell (PBSC) collection and improve patient outcomes by exacting a more potent direct anti-tumor effect prior to ASCT. Bendamustine (Treanda®) is a synthetic chemotherapeutic agent that shares structural similarities to both purine analog and alkylating agents without significant cross resistance to other compounds in either drug class. Bendamustine appears to have low stem cell toxicity in vitro, is well tolerated, and has activity in MM and NHL. We hypothesized that bendamustine9s activity in patients with disease resistant to first line therapies makes it a logical candidate for chemotherapy based PBSC mobilization. Methods: Patients were eligible if they had relapsed or refractory MM, B-cell NHL or T-cell NHL and were candidates for ASCT. Other criteria included: age >18 years, ANC >1,500/mm 3 , platelets >100,000/mm 3 , adequate renal and hepatic function, 2 IV d 1, 2 - provided along with financial support for this study by Teva Pharmaceuticals), etoposide (200 mg/m 2 IV d 1– 3), dexamethasone (40 mg PO d 1– 4), delivered as an outpatient, followed by filgrastim (10 mcg/kg/day; starting on d 5 through end of collection)]. Apheresis was initiated when peripheral blood CD34 cell counts were >5/μL. The primary endpoint was successful mobilization, defined as collection of >2.0 × 10 6 CD34 cells/kg. Adverse events (AEs) were graded using the CTCAE v4.0. Results: Twenty patients (16 MM, 3 B-cell NHL, 1 NK/T-cell NHL) were treated. The median age was 59 years (range 43–70), and the median number of prior therapies was 1 (range 1–3) for MM and 2 (range 2–3) for NHL patients. All patients (20/20) were successfully mobilized. The median number of CD34 + cells collected was 19.11 × 10 6 /kg (Mean 22.49; range 4.35 to 55.51 × 10 6 ). All MM patients collected >10 × 10 6 CD34 + cells/kg. The median time from BED mobilization therapy to the first day of CD34 stem cell collection was 12 days (mean 12.05; range 10 to 20 days). The median number of days of apheresis was 1 (mean 1.45; range 1 to 4). A predictable pattern of leucocyte nadir and recovery was demonstrated (88% of patients started apheresis between days 10–12). One patient (5%) was given plerixafor and for 2 patients (10%) the dose of GCSF was increased to 16 mcg/kg twice daily. Among the 20 patients mobilized and collected, 12 have thus far undergone ASCT and 100% (12/12) have achieved an unsupported neutrophil count >500/μL at an average of 14.3 days after PBSC infusion and a platelet count >20K/μL at an average of 10 days. Serious AEs (SAEs) were observed in 5 patients and 1 patient died due to disease progression. No unexpected grade 3 or greater treatment related SAEs were seen. Disease response assessments are ongoing. The original protocol design involved 3 agents (bendamustine, dexamethasone and GCSF [BDG]). After the first 3 patients enrolled, the mobilization regimen was modified to include etoposide because BDG did not yield a predictable pattern of leucocyte nadir and recovery, thus complicating timing for apheresis (median time to collection 22 days). The first 3 patients were censored from the analysis, however all 3 patients were successfully mobilized and collected. Conclusions: The initial experience with PBSC mobilization after BED in this phase II study suggests the regimen is safe and effective, while the use of BDG does not yield predictable CD34 kinetics. Time to neutrophil and platelet engraftment after ASCT appears unimpaired when compared with other chemotherapy based mobilization regimens. Large numbers of stem cells were rapidly mobilized and resulted in short durations of apheresis. No patient with MM collected 6 CD34 + cells/kg (sufficient for 2 ASCTs). The regimen was very well tolerated and these findings suggest that the role of bendamustine in PBSC mobilization should be further explored. Disclosures: Green: Teva Pharmaceuticals: Research Funding. Holmberg: Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding. Budde: Teva Pharmaceuticals: Research Funding. Gopal: Teva Pharmaceuticals: Research Funding
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Results of a Phase I-II Study of Fenretinide and Rituximab for Patients with B-Cell Lymphomas
Background:
Despite improved treatment options, indolent non-Hodgkin lymphoma (NHL) and Mantle Cell Lymphoma (MCL) remain incurable for most patients. Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR), an orally bioavailable synthetic retinoid, has been shown to induce apoptotic cell death in a variety of tumor types, presumably via intratumoral induction of oxygen free radicals. Our group has shown single-agent fenretinide anti-B-NHL activity as well as synergy with anti-CD20 antibody therapy when tested in vitro (Shan et al Clin Cancer Res . 2001) and in human xenograft models (Gopal et al, Blood 2004). These preclinical data support the first trial to evaluate this strategy of fenretinide and rituximab in patients with B-cell malignancies. Here we report results from a phase I-II study evaluating the safety and efficacy of fenretinide with rituximab for indolent NHL and MCL.
Methods:
This was an open-label, phase I/II study conducted at the Fred Hutchinson Cancer Research Center (FHCRC) and Seattle Cancer Care Alliance, Seattle, WA (ClinicalTrials.gov identifier: [NCT00288067][1]). The study was approved by the institutional review board at FHCRC and written informed consent was obtained from all patients. Major eligibility criteria included: CD20 positive lymphoid malignancy, radiographically measurable disease, ECOG PS ²2, and adequate organ function. The phase I portion evaluated the safety of dosing single agent fenretinide at 900 mg/m2 PO BID for days 1-5 of a 7 day cycle and allowed de-escalation for excess toxicity. The phase II portion added 375 mg/m2 IV rituximab weekly on weeks 5-9 then every 3 months. All patients could remain on therapy until disease progression or unacceptable toxicity. Response assessment occurred approximately every 3 months. Correlative studies included fenretinide pharmacokinetics, serum retinol concentrations, and evaluation of tumor expression of BCL-2 family proteins. Response was scored by standard criteria (Cheson 1999).
Results:
Thirty-two patients enrolled in the study: 7 patients in phase I, and 25 patients in phase II. The median age was 64 years (range, 40 - 78), 81% were male, and the median number of prior therapies was 1 (range, 0 - 10) with 22 (69%) having received prior rituximab and 8 (25%) with rituximab-refractory disease. Histologies included 13 CLL/SLL, 10 follicular (FL), 7 mantle cell (MCL), 1 lymphoplasmacytic, and 1 marginal zone. No dose limiting toxicities were observed in the phase I portion, and 900 mg/m2 was the dose level delivered in combination with rituximab for the phase II component. The most common treatment-related adverse events (AE) of any grade were reversible night blindness (n=18, 56%), other eye disorders (n=17, 53%), rash (n=12, 38%), and photosensitivity (n=8, 25%). The most common treatment related AEs of grade 3 or higher included: maculopapular rash, night blindness, and decreased lymphocyte count. Three patients (9%) discontinued treatment early due to toxicity (rash-2, GI toxicity-1). One patient with MCL in the phase I portion experienced stable disease (SD) lasting 35 months. In the phase II portion of the study, 5 (20%) patientOs disease responded (Figure), with 2 (8%) achieving complete remission (both SLL/CLL), and 3 (12%) achieving partial remission (2 FL, 1 MCL). In addition 16 (64%) patients had SD. The median progression-free survival was 9 months (range, 6 - 31 months), and the median overall survival was not reached (range, 33 months to not reached). Median time to progression of responders was 14.5 months. The one-month median peak and trough concentrations of fenretinide were 11.45 µM and 2.5 µM, respectively. Correlative studies assessing Bcl-2, BAX, and apoptosis in the 13 patients with circulating tumor cells were not able to associate these data with response, or survival.
Discussion:
In this phase I/II study, the combination of fenretinide and rituximab was well tolerated with predictable, reversible toxicities with up to 4.5 years of continuous therapy. Though the ORR was modest (20%), the majority had of patients had disease control (ORR + SD=84%) which lasted for > 6 months. Further study of this novel combination should focus on identifying the subset of B-NHL that is most likely to respond or the rational addition of other agents to augment these anti-tumor effects.
![Figure 1.][2]
Figure 1.
Disclosures Pagel: Actinium Pharmacetuicals, Inc.: Equity Ownership. Gopal: Merck: Research Funding; Emergent/Abbott: Research Funding; Cephalon/Teva: Research Funding; BioMarin: Research Funding; Sanofi-Aventis: Honoraria; Millenium: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Piramal: Research Funding; Biogen Idec, BMS: Research Funding.
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00288067&atom=%2Fbloodjournal%2F126%2F23%2F2728.atom
[2]: pending:ye
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Anti-CD45 Radioimmunotherapy Facilitates Donor Engraftment and Prolongs Survival in the Absence of TBI Prior to Haploidentical Bone Marrow Transplantation in a Disseminated Murine Leukemia Model
Abstract 4101 Background: Despite the curative promise of hematopoietic cell transplantation (HCT), many patients with hematologic malignancies relapse and others may not proceed to HCT due to the unavailability of a matched donor. Toxicities remain high with HCT, due in part to the administration of non-specific therapies such as total body irradiation (TBI) as part of preparative regimens. We aim to overcome these limitations by replacing TBI with anti-CD45 radioimmunotherapy (RIT) for haploidentical HCT to deliver radiation directly to leukemic cells while sparing normal organs and minimizing non-specific toxicities. Methods: We established an initial TBI HCT regimen in B6SJLF1/J mice (H-2D b haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). The mice then received 15 million donor (CB6F1/J, H-2D d ) BM cells (day 0), followed by cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Subsequent RIT HCT studies involved B6SJLF1/J mice conditioned with and without fludarabine (FLU) and escalating doses (200–400 μCi) of 90 Y-anti-CD45 Ab (30F11) RIT without TBI, followed by infusion of haploidentical BM cells from CB6F1/J mice and a single dose of cyclophosphamide (CY) 2 days after HCT. Chimerism studies were performed using flow cytometric analysis to assay for engraftment of donor CD8 + cells. Therapeutic studies were performed in B6SJLF1/J mice given 10 5 syngeneic leukemia cells via tail vein (day -5), followed by 200 or 400 μCi 90 Y-30F11 (day -3), and 1.5 × 10 7 BM donor cells (day 0) and two doses of CY (days -2 and +2) without FLU. Results: Using this model we have demonstrated that mixed chimerism was established in mice transplanted with TBI or escalating doses (200–400 μCi) of 90 Y-30F11 RIT followed by injection of haploidentical BM donor rescue cells. TBI-based HCT showed that chimerism as determined by flow cytometric analysis for donor CD8 + cells was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, and persisted ≥12 months. RIT-based HCT also revealed mice with mixed chimerism, with up to 89% of donor CD8 + cells 1 month after HCT. Elimination of FLU from the conditioning regimen did not significantly decrease chimerism, as mice transplanted without FLU showed up to 70% donor CD8 + cells 1 month after HCT. Subsequent RIT experiments in B6SJLF1/J mice harboring AML were treated with escalating doses of 90 Y-30F11 prior to HCT without FLU. Mice treated with anti-CD45 RIT using 200 μCi and 400 μCi of 90 Y-30F11 had a median overall survival (OS) of 73 (p 90 Y-30F11 group were euthanized on day 3 for excessive weight loss, without gross histology abnormality in kidneys or liver. Conclusion: These studies suggest that anti-CD45 RIT in the absence of TBI and FLU prior to haploidentical HCT can lead to establishment of mixed chimerism. Moreover, this anti-CD45 RIT in combination with haploidentical HCT can lead to improvement in survival for mice with AML. These results suggest that clinical studies with anti-CD45 RIT in lieu of TBI and FLU in a haploidentical HCT regimen should be considered for further investigation. Disclosures: No relevant conflicts of interest to declare
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Haploidentical Bone Marrow Transplantation Using Anti-CD45 Radioimmunotherapy to Decrease Relapse in a Pre-Clinical Murine Model
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Bendamustine (Treanda®)-Based Regimens Are Effective In Mobilizing Peripheral Blood Hematopoietic Stem Cells For Autologous Transplantation
Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for patients with advanced or treatment refractory multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Stem cell proliferation and mobilization can be enhanced though the addition of myelosuppressive chemotherapy prior to GCSF administration. Chemotherapeutic agents without cross resistance to prior therapies may support peripheral blood stem cell (PBSC) collection and improve patient outcomes by exacting a more potent direct anti-tumor effect prior to ASCT. Bendamustine (Treanda®) is a synthetic chemotherapeutic agent that shares structural similarities to both purine analog and alkylating agents without significant cross resistance to other compounds in either drug class. Bendamustine appears to have low stem cell toxicity in vitro, is well tolerated, and has activity in MM and NHL, but the potential for the purine moiety to adversely impact stem cell reserve is unknown. We hypothesized that bendamustine’s activity in patients with disease resistant to first line therapies makes it a logical candidate for chemotherapy based PBSC mobilization and tested its impact on stem cell yield. Methods Patients were eligible if they had relapsed or refractory MM, B-cell NHL or T-cell NHL and were candidates for ASCT. Other criteria included: age >18 years, ANC >1,500/mm 3 , platelets >100,000/mm 3 , adequate renal and hepatic function, 2 IV d 1, 2 - provided along with financial support for this study by Teva Pharmaceuticals), etoposide (200 mg/m 2 IV d 1- 3), dexamethasone (40 mg PO d 1- 4), delivered as an outpatient, followed by filgrastim (initially 10 mcg/kg/d sc; starting on d 5 through end of collection)]. Apheresis was initiated when peripheral blood CD34 cell counts were >5/µL. The primary endpoint was successful mobilization, defined as collection of >2.0 x 10 6 CD34 cells/kg. AEs were graded using the CTCAE v4.0. Results Thirty-seven patients (32 MM, 4B-cell NHL, 1 NK/T-cell NHL) were treated. The median age was 60 years (range 43-70). The median number of prior therapies was 1 (range 1-3) for MM and 2 (range 1-3) for NHL patients. All patients (37/37) were successfully mobilized. The median number of CD34 + cells collected was 19.43 x 10 6 /kg (range 4.35 to 55.51 x 10 6 ). All MM patients collected >10 x 10 6 CD34 + cells/kg. The median time from the start of BED mobilization therapy to the first day of CD34 stem cell collection was 12 days (range 9 to 20 days). The median number of apheresis days was 1 (range 1 to 4). A predictable pattern of leucocyte nadir and recovery was demonstrated (95% of patients started apheresis between days 9-13). Two patients (5%) were given plerixafor and for 2 patients (5%) GCSF was increased to 16 mcg/kg twice daily. Among the 37 patients mobilized and collected, 31 have thus far undergone ASCT and 100% (31/31) achieved an unsupported neutrophil count >500/µL at a median of 15 days (range 7-19) after PBSC infusion and a platelet count >20K/µL at a median of 11 days (range 8-14). Ten SAEs were observed in 8 patients and 1 patient died due to disease progression prior to ASCT. SAEs include: neutropenic fever (1, grade [GR] 3), bone pain (2, GR 3), renal insufficiency (1, GR 1), atrial fibrillation (1, GR 2), hypotension (1, GR 3), stroke (1, GR 2), and one patient accounted for 3 SAEs including GR 3 tumor lysis syndrome and sepsis and GR 5 disease progression. Among twenty-nine evaluable patients to date, responses include: CR= 4 PR=2, SD=19 and PD=4. The ORR to this single cycle of therapy was 21%. Conclusions PBSC mobilization with BED is safe and effective. BED is not an acute stem cell toxin. Large numbers of stem cells were rapidly mobilized and resulted in short durations of apheresis. No patient with MM collected 6 CD34 + cells/kg (sufficient for 2 ASCTs). Twenty-one percent of patients demonstrated a measurable response to a single cycle of BED therapy and an additional 65% of patients had stable disease. In patients who were transplanted, the time to neutrophil and platelet engraftment was comparable to other chemotherapy based mobilization regimens. The BED regimen was well tolerated and these findings suggest that the role of BED in PBSC mobilization should be further explored. Disclosures: No relevant conflicts of interest to declare
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Anti-CD45 Radioimmunotherapy Using the Alpha-Emitting Radionuclide 211At Combined with Bone Marrow Transplantation Prolongs Survival in a Disseminated Murine Leukemia Model
Abstract 4096 Background: Despite aggressive hematopoietic cell transplant (HCT) strategies, many patients with acute myeloid leukemia (AML) relapse. Our group has explored radioimmunotherapy (RIT) using anti-CD45 antibodies (Ab) labeled with β-emitting radionuclides such as 131 I and 90 Y as a means to augment cytotoxicity and reduce relapse. This approach has been limited by their low energy levels (0.66–2.3 MeV) and potential non-specific toxicities due to their relatively long path lengths (0.3–2.3 mm). Conversely, α-emitting agents display higher energy levels (8 MeV) delivered over a short path-length (∼60–80 μm) that can lead to superior therapeutic ratios of absorbed radiation doses that may reduce AML relapse. For this purpose 211 At is an α-emitter with an attractive half-life (7.2 hours), energy profile (6.8 MeV averages of two alpha decays, 5.9 and 7.5 MeV) and path length (average range 55–70 μm). Therefore, we evaluated the efficacy and toxicity of anti-CD45 RIT using 211 At in a clinically relevant CD45 + disseminated murine leukemia model. Methods: SJL/J mice were given 10 5 syngeneic SJL leukemic peripheral blood mononuclear cells (PBMCs) via tail vein, followed two days later by 211 At-labeled anti-murine CD45 Ab-decaborate(2-) conjugate (30F11-B10) or 211 At-labeled negative control Ab-decaborate(2-) conjugate (rat IgG-B10) in tissue biodistribution studies. Groups of 5 mice were euthanized 6, 24 and 48 hours later and organs were harvested and analyzed in a gamma counter to yield percent of the injected dose per gram (% ID/g). To assess toxicities associated with this approach, SJL/J mice were treated with 12–24 μCi of 211 At-30F11-B10 and then evaluated weekly thereafter for impact on blood counts, as well as changes in hepatic and renal function. In HCT therapeutic studies, groups of 10 leukemic mice per dose were injected with 12–24 μCi of 211 At-30F11-B10 or 211 At-rat Ab-B10, followed two days later by rescue with 15 × 10 6 syngeneic bone marrow (BM) cells. Results: Delivery of 211 At-30F1-B10 demonstrated excellent localization to the BM and spleen at 24 hours (79 and 18% ID/g, respectively) post injection with lower kidney and lung uptake (8.4 and 8.3% ID/g, respectively) at the same time point. Anti-CD45 RIT using 211 At-30F11-B10 followed by syngeneic HCT led to a dose-dependent survival benefit in leukemic mice with a median survival (OS) of 120, 98 days, and 62 days for animals treated with 24, 20, and 12 μCi 211 At-30F11-B10, respectively, compared with untreated control mice (median OS of 36 days) and mice treated with non-specific 211 At-labeled rat Ab-B10 (median OS of 46 days) (Figure). Moreover, anti-CD45 RIT with 211 At-30F11-B10 led to minimal toxicity with mild dose dependent leukopenia as the most pronounced lab abnormality. White blood cell count nadir was between 2.5 and 4.2 k/μL two weeks after HCT for mice treated with 24 and 12 μCi 211 At-30F11-B10, respectively. Counts recovered to normal levels (6–8 K/μL) 4 weeks after HCT. Mild increases in transaminase levels were seen in mice that received 211 At-30F11-B10, yet these values remained within the normal ranges (ALT 68–75 IU/L; AST 155–170 IU/L). Renal function after 211 At-30F11-B10 did not significantly deviate from baseline (BUN 15–17 mg/dL; Cr 0.3–0.4 mg/dL). Conclusion: Taken together, these data suggest that anti-CD45 RIT using the α-emitting radionuclide 211 At in conjunction with HCT is a promising therapeutic option for AML. Excellent targeting of radiation doses to BM and spleen was demonstrated with a favorable toxicity profile. Further investigation of anti-CD45 RIT for AML using 211 At in clinical trials appears to be warranted. Disclosures: No relevant conflicts of interest to declare