Prior Salvage Regimens Research Articles

PB1831: UTILITY OF FLT3 INHIBITORS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) AND T(6;9)(P22;Q34)

Background: Efficacy of FLT3 inhibitors in patients (pts) with AML and t(6;9)(p22;q34)/DEK-NUP214 is not well established. Aims: We compared overall survival (OS) and event-free survival (EFS) of AML pts with t(6;9) who received FLT3 inhibitor (FLT3-i) in frontline (FL) or salvage (SL) setting, regardless of their FLT3 mutation status. Methods: We retrospectively evaluated pts with AML or high-risk Myelodysplastic Syndrome (HR-MDS) who presented to our center between 1995-2021. Among 9936 pts, 55 pts (0.5%) had t(6;9) (48 AML, 7 HR-MDS). In FL setting, pts were divided according to their induction regimen with (n:5) or without FLT3-i (n:48). In SL setting, 35 pts who relapsed or were refractory to FL regimen were recategorized according to their SL regimen with (n:16) or without FLT3-i (n:17). Four pts were excluded from analysis due to incomplete data. Results: Among 47 pts with available molecular data, 35 (74%) was FLT3-ITD+, 5 (10.6%) with both ITD and TKD mutation. ITD allelic ratio (AR) was known for 28 (80%) pts (AR range: 0.01-0.95) with 11 (31%) pts having an AR ≥0.5. Age was well-balanced across all cohorts with median of 41 years (yr). Most pts had ECOG performance status of 0-1 (92%) on presentation. Pts with FLT3-ITD mutation were more likely (83%) to receive intensive chemotherapy (IC) compared to pts without (50%, p=0.02). Most pt in FL cohort with or without FLT3-i received IC (80% and 77%, respectively). There was no significant different in FLT3-ITD positivity between FL cohort with or without FLT3-i (p=0.3). Sorafenib was used in 62% of cases, followed by Quizartinib (24%). All pts in FL cohort with FLT3-i achieved CR/CRi with 60% MRD negative rate as compared to 52% in non-FLT3-I, and 60% of FLT3-i cohort had stem cell transplantation (SCT) in CR1 (vs. 21% of non-FLT3-i). Median number (No.) of therapy cycle was 1 to reach CR/CRi in all FL cohorts. Outcomes are shown in Figure 1. With median follow up of 47 months (mos), 2-yr OS and EFS were higher in FLT3-i than non-FLT3-i cohort (80% and 60% vs. 41% and 20%, respectively), although not statistically significant (p=0.2 for OS and 0.1 for EFS). Among pts with known mutation status, there were non-significant lower 2-yr OS and EFS in FLT3-ITD+ pts than wild-type FLT3 (FLT3-wt) pts (44% and 22% vs. 58% and 42%, respectively; p=0.4 for OS and 0.3 for EFS), regardless of whether FLT3-i was included in the induction regimen. CR/CRi rate was similar between FLT3-ITD+ (57%) and FLT3-wt pts (58%) but FLT3-wt pts was more likely to receive SCT in CR1 (42%) than FLT3-ITD+ pts (23%). In SL setting, 75% pts in FLT3-i cohort received low intensity therapy as compared to 12% pts in non-FLT3-i cohort (p<0.01) and 69% pts in SL cohort without FLT3-i were FLT3-ITD+ (p=0.03). Pts were heavily treated in both group (67% pts were in salvage 2+), but never received FLT3-i as part of their prior salvage regimen. No. of prior therapies and proportion of pts with prior SCT and FLT-i- containing induction regimen were similar across cohort. CR/CRi rate was higher in FLT3-i cohort (69%) than non-FLT3-i cohort (41%) after median No. of 1 therapy cycle with similar proportion of pts who went to SCT post salvage regimen. With median follow up of 47 mos, 2-yr OS and EFS were poor in both FLT3-i cohort and non-FLT3-i cohort (27% and 12% vs. 12.5% and 6%, respectively, p=0.3 for OS and 0.7 for EFS). Image:Summary/Conclusion:FLT3 mutation status does not impact survival in pts with t(6;9). Addition of FLT3-i to FL and SL regimen in subset of pts with FLT3-ITD mutation is beneficial and should be further evaluated.

HL-215: Short-Course Nivolumab as a Bridge to Stem Cell Transplant is Effective in Refractory Hodgkin Lymphoma

Context Immune checkpoint inhibitors are effective in the setting of HL with relapse after autologous transplant, in disease refractory to Brentuximab, and upfront in advanced stage disease. PD-1 blockade is an expensive treatment option; therefore, truncated dosing schedules are relevant. Objective To describe efficacy and toxicity profile of short-course nivolumab in the setting of refractory lymphoma. Design Retrospective analysis. Patient Population Relapsed/primary progressive lymphoma, refractory to 2 lines of salvage therapy. Intervention Nivolumab 3 mg/kg; IV every 2 weeks. Main outcome measures (1) Remission status and transplant eligibility; (2) incidence of immune-related adverse events. Results 29 patients with refractory lymphoma, with median of 2 prior salvage regimens, received nivolumab between 2015-2019. HL: Fifteen patients with refractory HL. Combination therapy (lenalidomide) was given in 5 patients. 12 out of 13 patients reassessed by PET/CT were transplant-eligible [Deauville score Conclusions HL responds well to short course nivolumab, permitting consolidation with stem cell transplant, and is a cost-effective strategy that should be studied further in relapsed/refractory HL. DLBCL has a poor response to immune checkpoint blockade, and alternate therapies must be sought. Immune-related adverse events are rare with short-course therapy. Limitations Retrospective nature of this study limits conclusions, however further study in this setting is warranted. Disclosures None to be made.

ABCL-014: Gemcitabine and Docetaxel Protocol as Intent to Autologous Bone Marrow Transplantation in Patients with Refractory and Relapsed Non-Hodgkin Lymphoma: Single Institutional Prospective Phase II Study

Context: Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for relapsed/refractory (R/R) DLBCL. However, 50% of the patients are not eligible for transplant due to failure of salvage treatment. Gemcitabine and docetaxel as single agents had shown activity in R/R lymphoma with response rates (RR) ranging from 13-70%. Objective: We investigated whether adding docetaxel to gemcitabine (GemDoc regimen) could salvage patients with R/R-DLBCL under consideration for ASCT, who failed at least one prior salvage regimen. Design: Our study is a prospective phase II, nonrandomized study between January 2016 and June 2019. Setting: It was carried out at Oncology Center Mansoura University (OCMU). Patients: The study was carried out on 41 patients of refractory and relapsed non-Hodgkin lymphoma. Interventions: Treatment consisted of gemcitabine 1 gm/m2 and docetaxel 35 mg/m2intravenous on days 1 and 8 which were repeated every 3 weeks in outpatient setting. Main outcomes measures: We analyzed our data on personal computer running IBM SPSS© for windows (Statistical Package for Social Scientists) Release 20. We considered two-tailed p-value less than 0.05 as statistically significant. Results: Forty-one eligible patients (29 males; 70.7%) with R/R NHL were treated with GemDoc. The median number of treatment cycles was 3 (1-6). After treatment there were 3 patients in complete responses (7.3%) and 18 with partial responses (43.9%). The overall RR was 52.2%. Five patients proceeded to ASCT. The most common toxicities related to this protocol were anemia (61% of patients), thrombocytopenia (53.7% of patients), neutropenia (41.5% of patients) and hepatotoxicity (26.8% of patients). Treatment-related mortality occurred in 4 patients; all were > 50 years and were positive for HCV infection. The median EFS of studied cases was 3 months and the median OS was 6 months. The outcomes were not affected by previous use of gemcitabine, nor the number of previous salvage regimens. Conclusion: GemDoc has limited activity as a salvage regimen in R/R NHL. It could salvage few carefully selected heavily pretreated patients with intent to proceed to ASCT.

Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2:2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3e on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. Disclosures Roboz:Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

S877 SAFETY AND CLINICAL ACTIVITY OF AMV564, A CD33/CD3 T‐CELL ENGAGER, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML): UPDATED RESULTS FROM THE PHASE 1 FIRST‐IN‐HUMAN TRIAL

Background:AMV564 is a novel bivalent, bispecific (2:2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T‐cell receptors. AMV564 creates an immune synapse between CD33‐expressing cells and T cells, initiating T‐cell directed lysis of CD33 expressing cells, and inducing activation, differentiation and proliferation of T cells. In preclinical studies, AMV564 eliminated myeloid blasts with picomolar potency and demonstrated broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016; 22:5829–38).Aims:The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti‐leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), assessment of cytokine changes, and immunophenotyping of T cells and myeloid cells are secondary objectives.Methods:This is an ongoing Phase 1 study with a 3+3 dose‐escalation followed by a dose expansion (NCT03144245). The key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1–2 prior induction regimens (with a standard anthracycline‐based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days in a 28 day cycle. Responding patients are eligible to receive additional cycles until disease progression or unacceptable toxicity. AMV564 and cytokine concentrations are measured by validated immunoassays and immunophenotyping is performed by flow cytometry.Results:To date, 30 patients (16 male/14 female) with a median age of 72 years (range 24–84 years) have been enrolled in 8 dose cohorts from 0.5 to 200 mcg/day. Twenty‐two patients (73%) had secondary AML and/or adverse cytogenetics, including 9 patients (30%) with a p53 mutation. Nineteen patients (63%) had received at least 1 prior salvage regimen and 18 (60%) had received prior intensive chemotherapy, including 9 patients (30%) who had received a high‐dose (≥ 1 g/m2) cytarabine‐based regimen. At the time of this analysis, 28 patients were evaluable for safety and 27 patients were evaluable for activity. No dose‐limiting toxicity or treatment‐related Grade ≥ 3 adverse events (AE) were reported. Using a lead‐in dose regimen, Grade 2 CRS was observed in 1 patient (treated at 200 mcg/day) and no Grade 3 or higher CRS has been observed. The most common Grade ≥3 treatment‐emergent AE has been febrile neutropenia, reported in 9 (30%) of 30 patients. No patient has died within 30 days of treatment initiation. Bone marrow blast reductions were observed in 17 (63%) of 27 efficacy evaluable patients. At doses of 100 mcg or higher, objective responses (1 complete response [CR], 1 CR with incomplete hematologic recovery, and 1 partial response) were observed in 3 of 9 evaluable patients. AMV564 PK was dose proportional with a terminal half‐life of 2–3 days. Serum concentrations increased gradually, with times to steady‐state concentration of 3–7 days. Marked increases in serum IL6, IL8, and IL10 were observed with evidence of T‐cell activation in both blood and bone marrow.Summary/Conclusion:AMV564 is well‐tolerated and demonstrates anti‐leukemic activity through T‐cell engagement using a 14‐day administration schedule. AMV564 has a unique PK profile with a gradual increase in drug concentrations and thus the potential for better controlled T‐cell activation.

Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

▪Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38).Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR.Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level.Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. DisclosuresRoboz:Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

Low Efficacy and High Mortality Associated with Clofarabine Treatment of Patients with Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes

Background: Clofarabine, a second-generation nucleoside analogue, has been shown in prospective studies to have activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of the drug in populations of patients not enrolled in clinical trials.Methods: We reviewed clinical outcomes for 84 patients treated at our center off-study for relapsed or refractory AML (n=81) or MDS (n=3) with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Almost all patients (n=62) receiving combination therapy were administered cytarabine 1 g/m2/day on days 1-5 and clofarabine 40 mg/m2/day on days 2-6 (Faderl et al Blood 2005; 105:940), while monotherapy dosing ranged from 15-30 mg/m2/day x 5 days.Results: Median age of patients was 51 years; 54% were male. The median prior salvage regimens received was 1 (range, 0-5). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR = CR + CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal significant variation in response rates when comparing age, performance status, or prior number of salvage regimens. 30-day mortality or induction death for all patients, combined therapy, and monotherapy was 21%, 23%, and 16% respectively. Overall median survival for all patients was 3 months; a subset of 12 patients who were able to go to allogeneic stem cell transplant had an 18-month median survival.Conclusion: Clofarabine’s efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. Clofarabine’s utility in relapsed/refractory AML/MDS may be primarily for cytoreduction in patients who have an allogeneic transplant option. DisclosuresOff Label Use: Clofarabine- a second-generation nucleoside analogue approved for pediatric acute lymphoblastic leukemia..

Safety and Efficacy of Marqibo (Vincristine Sulfate Liposomes Injection, OPTISOME™) in for the Treatment of Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL).

Introduction: Vincristine sulfate (VCR) is a lipophilic, cell-cycle specific, antineoplastic agent that inhibits cell division by specifically binding to tubulin in mitotic spindles. The activity of VCR is dose and time-dependent, but central and peripheral neuropthy prohibits its use beyond doses of 1.4 mg/m2 (capped at 2 mg). Marqibo is a formulation of VCR encapsulated in a sphingomyelin/cholesterol liposome (OPTISOME) with a longer half-life than VCR. In murine models using L1210 or P388 lymphoid leukemia cell lines, Marqibo demonstrated greater anti-tumor activity compared with VCR. Marqibo was therefore an appropriate agent to study in relapsed or refractory ALL.Methods: Two clinical trials have been completed. First, a phase II trial of single agent Marqibo given at 2 mg/m2 (no dose capping) every 2 weeks enrolled 16 patients (pts) [Thomas et al, Cancer 106:120, 2006]. A multicenter dose escalation phase I trial using weekly Marqibo (1.5, 1.825, 2.0, 2.25, 2.4 mg/m2) in combination with pulse dexamethasone followed. There were no restrictions on the number of prior therapies. Subjects with grade 2 or greater central or peripheral neuropathy were ineligible.Results: In total, 52 pts with relapsed or refractory ALL were treated in the two studies combined. Median age was 34 years (range, 19–77), 31 males/21 females, with a median number of prior salvage regimens of 2 (range, 1–3). Nine pts had confirmed Philadelphia positive disease (8 in the pre-imatinib era, 1 resistant to tyrosine kinase inhibitor therapy). All pts had previously received conventional VCR therapy. There were 8 complete remissions and 3 partial remissions for an overall response rate of 21% [95% CI, 11, 35]. An additional 12 pts (23%) achieved hematological improvements (e.g., clearance of marrow blasts, platelet transfusion independence). Five responders were able to undergo allogeneic stem cell transplantation following therapy with Marqibo. The maximum tolerated dose in the phase I trial was 2.25 mg/m2 owing to grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity observed in 1 patient each at the 2.4 mg/m2 dose level. Grade 1–2 peripheral neuropathy was manageable with dose modifications and anti-neuralgia agents such as gabapentin. Commonly observed toxicities included febrile neutropenia, myelosuppression, abdominal pain, nausea, constipation, diarrhea, fatigue, and infusion-related pyrexia.Conclusions: In reviewing the clinical experience to date, Marqibo with or without pulse dexamethasone has provided clinically meaningful activity in heavily pre-treated adults with ALL. A multicenter trial of single agent Marqibo in the setting of second salvage therapy for adults with relapsed ALL is underway. A phase III multicenter trial of Marqibo in combination with standard chemotherapy for de novo elderly ALL is in the planning phase.

Gallium, rituximab, and dexamethasone for relapsed NHL

8079 Background: Almost 50% of patients with intermediate grade non-Hodgkin's lymphomas (NHL) treated with standard CHOP- like therapy will have less than a complete response (CR) after treatment or will relapse after obtaining a CR. Salvage chemotherapy followed in responders by an autologous stem cell transplant (ASCT) can be curative. For many patients, this is not an option due to age, comorbidities, or lack of response. A non-cross resistant agent with activity in NHL which could salvage more patients is gallium nitrate Methods: We conducted a phase II clinical trial investigating the combination 3 non-myelosuppressive agents, gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. Gallium is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients had relapsed or refractory disease and had a SWOG PS ≤3. Patients may have failed prior ASCT or allogeneic SCT. This was a 2 stage, phase II study with initial evaluation after 22 patients of whom at least 10 responders were needed for completion of the study, as determined prior to start of trial Results: We enrolled 22 patients on study. 15 had large cell, 6 had transformed follicular and 1 had mantle cell NHL. Most of these patients were refractory to one or several prior salvage regimens [13/22 (59%)]; all had prior rituximab 22/22 (100%) and 18/22 (82%) had it with there most recent treatment. No patients developed grade 3 or 4 toxicities, except grade 4 lymphopenia in 7/22 (32%). The overall response rate was 10/22 (45%); CR/CRu 8/22 (36%); PR 2/22 (9%); SD 4/22 (18%); and PD 8/22 (36%). Five patients went on to receive stem cell transplant (including 3 allogeneic and 2 ASCT). Two of the responders were patients who had failed a prior stem cell transplant: 1 ASCT failure who remains in CR &gt;18 months and an allograft failure in CR &gt;14 months after relapse. Of the 22, 10 (46%) are alive at a median f/u of 17.2 months, of whom 7 are currently NED Conclusions: This regimen appears to be effective and relatively non-toxic for patients with relapsed and refractory NHL, including stem cell transplant failure. As CR at ASCT may be associated with an improved outcome, a trial of GaRD combined with RICE is planned to improve cytoreduction prior to ASCT in patients with relapsed NHL. No significant financial relationships to disclose.

Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer 106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

The combination of gallium nitrate, rituximab and dexamethasone is effective and safe as a salvage regimen for diffuse large B-cell lymphoma

17510 Background: More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. As our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s and it has been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with transferrin and/or transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. Methods: The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS ≤3. Patients may have failed prior ASCT or allogeneic SCT. The accrual goal was 37 patients however the study was stopped after 22 patients were accrued as the primary endpoint was reached after the initial interim analysis. Results: ORR 12/22 (55%); CR/CRu 6/22(27%); PR 6/22(27%); SD 3/22 (14%); and PD 7/22 (32%). Most of these patients were refractory to prior salvage regimens 15/22 (68%), including ESHAP, DHAP or high-dose cyclophosphamide. No patients developed grade 3 or 4 toxicities, with the exception of grade 4 lymphopenia. Conclusions: Gallium nitrate, rituximab and dexamethasone (GaRD) appears to be an effective and non-toxic salvage regimen for patients with relapsed DLBCL [Table: see text]

Novel Combination of Gallium Nitrate, Rituximab and Dexamethasone for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Transformed Follicular Lymphoma.

More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. Despite advances in treatment modalities such as radiation, biologic agents, and cytotoxic chemotherapeutic regimens, only 25–30% of these patients will be cured of their disease. Standard salvage regimens such as DHAP, ESHAP, ICE and EPOCH have proven efficacy at the cost of increasing toxicity and hospitalization costs. The reported response rates for these are on the order of 50–75% as first-line salvage regimens. However, as our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s. While it is currently approved for the treatment of bisphosphonate resistant hypercalcemia of malignancy, it has also been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with the transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS &lt;3. Patients may have failed prior ASCT or allogeneic SCT. The accrual goal is 37 patients. We have enrolled 14 patients on study to date and have 12 evaluable patients; as part of the ongoing safety evaluation for this study, we have the following results: ORR 9/12 (75%); CR 2/12 (17%); PR 7/12 (58%); SD 2/12 (17%); and PD 1/12 (8%). Most of these patients were refractory to prior salvage regimens 8/12 (67%), including ESHAP, DHAP or high-dose cyclophosphamide. No patients developed grade 3 or 4 toxicities, with the exception of grade 4 lymphopenia and grade 3 anemia (most likely due to transferrin receptor binding). Conclusions: gallium nitrate, rituximab and dexamethasone (GaRD) appears to be an effective and relatively non-toxic salvage regimen for patients with relapsed DLBCL, MCL or transformed FL.

Preliminary Results of Phase I Trial of Sphingosomal Vincristine (SV) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

New and more effective agents are needed to improve treatment outcome for patients with relapsed or refractory ALL. Vincristine is active in ALL, but its free form has a half-life of 6–12 minutes and the dose is usually capped at 2 mg due to severe neurotoxicity. Sphingosomal vincristine (SV, vincristine encapsulated in sphingomyelin liposomes or “sphingosomes”) has a circulation half-life of 12 hours in humans and is more active than free vincristine in mice bearing P388 and L1210 leukemias. In clinical trials, SV was active in relapsed aggressive lymphomas with limited neurotoxicity (Sarris et al, Annal Oncol 10:35, 1999). A small study of single agent SV 2.0 mg/m2 without dose capping given every 2 weeks was conducted in previously treated ALL, and objective responses were observed in 14% (95% CI, 2% to 48%) of 16 heavily pretreated patients (pts) (Thomas et al, Blood 94:238b, 1999).Methods: A phase I clinical trial of weekly SV (dose escalated with 3 subjects in each cohort and expansion to 6 for toxicity) with pulse dexamethasone 40 mg daily days 1–4 and 11–14 was initiated. From August 2002 to July 2004, 17 pts with relapsed or refractory ALL without greater than grade 2 prior or active central or peripheral neuropathy (PN) were enrolled. Pts had to complete one course (defined as 4 weekly doses of SV) to be assessed for maximum tolerated dose (MTD). Five pts were treated with weekly SV 1.5 mg/m2, 3 at 1.825 mg/m2, 3 at 2.0 mg/m2, and 6 at 2.25 mg/m2.Preliminary results: Median age of the group was 31 years (range, 21– 62). Thirty percent were refractory to induction therapy. Median number of prior salvage regimens was 2 (range, 0 – 3). Of the 14 pts evaluable for response to SV (3 too early), 4 (29%) achieved complete remission (CR) (2 at 1.5 mg/m2, 1 at 1.825 mg/m2 and 1 at 2.25 mg/m2) and 2 (14%) achieved hematologic improvement (clearance of circulating leukemia cells and transfusion independence of platelets) after 2 courses, but were removed from study for persistent leukemia. Eight pts (57%) either progressed (PD) or failed to respond. Two pts discontinued therapy early (1 for PD after 3 doses of SV and 1 withdrew consent after 3 doses), and 1 pt had therapy interrupted after 1 dose of SV owing to C. difficile colitis. One CR pt relapsed after 3 months and achieved third CR with hyper-CVAD followed by allogeneic stem cell transplant (SCT). Three pts went on to SCT while in CR (1 died after sepsis). Non-hematologic toxicities attributed to SV included grade 1–2 PN in nearly all pts and tumor lysis syndrome in 1 pt. Five pts had transient grade 3–4 elevations in hepatic transaminases attributed to azole antifungal prophylaxis. Grade 3 infections (e.g., bacteremia or fungal processes) were related to baseline neutropenia in 6 pts and SV-induced neutropenia in 4 pts. Enrollment continues with plan for continued dose escalation of weekly SV with no dose-limiting toxicities observed to date.Conclusion: Encouraging preliminary results suggest activity of SV with dexamethasone in relapsed and refractory ALL with dose intensification.

Mitoxantrone and prolonged infusion gemcitabine as salvage therapy in patients with acute myelogenous leukemia

In a recent phase I study, a combination of gemcitabine at 10 mg/(m 2 min) for 12 h and mitoxantrone 12 mg/m 2 daily for 3 days, achieved a complete remission (CR) in 3 of 12 (25%) patients with refractory leukemia. A pilot assessment of this regimen was conducted to determine its tolerability in patients with refractory acute myeloid leukemia (AML). In a cohort of 18 patients with very refractory disease (6 primary refractory, 12 relapsed, mean initial CR duration 3.5 months), one patient achieved a CR, a second CR with incomplete platelet recovery (CRp). Sepsis and mucositis were significant extramedullary toxicities. The gemcitabine and mitoxantrone regimen was feasible to administer even in heavily pre-treated patients. It was not active in patients who had failed a prior salvage regimen. It may warrant further study in patients with primary resistant AML.

The Costs and Efficacy of Liposomal Doxorubicin in Platinum-Refractory Ovarian Cancer in Heavily Pretreated Patients

Objective. In clinical practice, chemotherapy agents demonstrating modest second-line activity against platinum-refractory epithelial ovarian cancer (PROC) are frequently used in patients who have received multiple prior chemotherapy agents. Whether the response rates reported in selected patients can be expected in heavily pretreated patients is not known. Similarly, the costs of palliative chemotherapy are not known. We sought to determine the response, survival, and predictors of response in an unselected cohort of PROC patients receiving liposomal doxorubicin (LD) for relapsed disease, and the overall costs of delivering liposomal doxorubicin in this setting.Methods. In a cohort of 62 consecutive patients who initiated LD as second- or greater-line therapy for PROC, the following variables were examined: age, number of prior regimens for relapse disease, duration of first clinical remission, time from last prior treatment, dose intensity of LD received, response/clinical benefit, time to progression, toxic effects, and survival. Multivariate analyses were used to identify predictors of clinical benefit and overall survival. Direct medical charges were calculated and converted to costs, and major cost drivers determined.Results. Sixty-two patients received a total of 174 cycles of LD. The mean number of cycles per patient was 2 (range, 1–8); the median number of prior regimens for recurrent PROC was 2 (range, 0–8); and the median duration of the first clinical remission was 6 months. Median dose intensity of LD delivered was 11.4 mg/m2/week (range, 2.8–16.7 mg/m2/week). Nine of sixty-two patients (14.5%) had an objective clinical response by CA-125 and/or CT scan (95% confidence interval, 6–23%). Grade 3/4 toxicity occurred in 11% of patients. In the full cohort, median time to progression was 2.2 months, and median overall survival, 9.6 months (range, 0.2–26 months). Dose intensity was the only independent predictor of overall response. Duration of first clinical remission and number of prior salvage regimens were associated with longer overall survival. The mean total direct medical cost per cycle of LD was $5763, and the major cost drivers were hospitalizations and drug acquisition/delivery costs.Conclusion. LD is an active agent in PROC, even when used as greater-than-second-line therapy. Among heavily pretreated patients, delivering a dose intensity of at least 9.0 mg/m2/week was associated with a higher probability of response. The cost per cycle of LD is driven by hospitalizations and drug acquisition/delivery costs.