Ann Mohrbacher

A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma

This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

Phase I Trial of Anti-CS1 Monoclonal Antibody Elotuzumab in Combination With Bortezomib in the Treatment of Relapsed/Refractory Multiple Myeloma

PURPOSE To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM). PATIENTS AND METHODS Elotuzumab (2.5, 5.0, 10, or 20 mg/kg intravenously [IV]) and bortezomib (1.3 mg/m(2) IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria. RESULTS Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months. CONCLUSION The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM.

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

B cell non-Hodgkin's lymphoma: rituximab safety experience

A substantial body of data supports use of rituximab as first-line and maintenance therapy for the treatment of indolent non-Hodgkins lymphoma. With 7 years of postmarketing surveillance experience and more than 370,000 patient exposures, the safety profile of rituximab is well defined. Several multicenter trials suggest that infusion reactions associated with rituximab administration are well characterized and generally associated with the first infusion; toxicity is reduced with subsequent doses. Since some adverse events are related to circulating tumor loads of non-Hodgkins lymphoma, fewer events are anticipated in rheumatoid arthritis. Low infection rates in oncology would indicate similar safety in patients with rheumatoid arthritis.

Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial

Vascular endothelial growth factor (VEGF) is upregulated in multiple myeloma (MM), and circulating VEGF levels may correlate with response to therapy (Hideshima, et al 2005, Pittini, et al 2002). Thalidomide has been part of the standard treatment for MM and is thought to inhibit VEGF-associated angiogenesis (Du, et al 2004). Bevacizumab, a monoclonal antibody directed against VEGF-A, inhibits VEGF (Jenab-Wolcott and Giantonio 2009). Accordingly, we set out to test the efficacy and safety of bevacizumab alone and in combination with thalidomide in MM patients.

Toxicity profile of repeated doses of PEG-asparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia.

Despite having been long regarded as too toxic for adult patients, pediatric‐like regimens containing L‐asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated‐asparaginase (PEG‐asp) in adults, we reviewed all doses (2000 IU/m2) administered as part of a pediatric‐inspired regimen in adult ALL at our center. Subjects aged 18–60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3–4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3–4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG‐asp was always discontinued after grades 3–4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG‐asp dosing is safe in adults aged 18–60 yr, even after occurrence of a drug‐related toxicity.

A phase I biological study of azacitidine (VidazaTM) to determine the optimal dose to inhibit DNA methylation

This study aims to determine the optimal dosing and administration route for azacitidine to reduce global DNA methylation levels in the peripheral blood of patients with hematologic malignancies. Seventeen patients were enrolled into one of five dose level treatment groups (3 at 25mg/m2, 4 at 50mg/m2, 4 at 75mg/m2, 3 at 100mg/m2, and 3 at 150mg/m2) and received IV azacitidine at their respective dose on days 1-5 of cycle one. All patients received 75mg/m2/day IV on days 1-5 of cycle 2. Subcutaneous dosing of 75mg/m2/day on days 1-5 was used in cycle 3. Peripheral blood was collected on days 1, 3, and 5 of each cycle, and global DNA methylation was measured using bisulfite-PCR pyrosequencing of the DNA repetitive element LINE-1. 14 patients were evaluable for response with 2 CR, 2 PR, 7 SD and 3 PD reported. LINE-1 DNA methylation decreased by 1.37, 2.29, 4.81, 1.94 and 4.05% on day 5 for the 25mg/m2, 50mg/m2, 75mg/m2, 100mg/m2 and 150mg/m2 cycle one dose levels respectively. Mean decrease in LINE-1 DNA methylation was 3.7% with 75mg/m2 IV and 3.4% by subcutaneous adminstration. The data indicates that 75mg/m2 azacitidine given IV or SC effectively leads to global DNA methylation reduction by LINE-1 analysis.

HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia: Results From the Microtransplantation Interest Group

Importance The outcome of older patients with acute myeloid leukemia (AML) remains unsatisfactory. Recent studies have shown that HLA-mismatched microtransplant could improve outcomes in such patients. Objective To evaluate outcomes in different age groups among older patients with newly diagnosed AML who receive HLA-mismatched microtransplant. Design, Setting, and Participants This multicenter clinical study included 185 patients with de novo AML at 12 centers in China, the United States, and Spain in the Microtransplantation Interest Group. Patients were divided into the following 4 age groups: 60 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 85 years. The study period was May 1, 2006, to July 31, 2015. Exposures Induction chemotherapy and postremission therapy with cytarabine hydrochloride with or without anthracycline, followed by highly HLA-mismatched related or fully mismatched unrelated donor cell infusion. No graft-vs-host disease prophylaxis was used. Main Outcomes and Measures The primary end point of the study was to evaluate the complete remission rates, leukemia-free survival, and overall survival in different age groups. Additional end points of the study included hematopoietic recovery, graft-vs-host disease, relapse rate, nonrelapse mortality, and other treatment-related toxicities. Results Among 185 patients, the median age was 67 years (range, 60-85 years), and 75 (40.5%) were female. The denominators in adjusted percentages in overall survival, leukemia-free survival, relapse, and nonrelapse mortality are not the sample proportions of observations. The overall complete remission rate was not significantly different among the 4 age groups (75.4% [52 of 69], 70.2% [33 of 47], 79.1% [34 of 43], and 73.1% [19 of 26). The 1-year overall survival rates were 87.7%, 85.8%, and 77.8% in the first 3 age groups, which were much higher than the rate in the fourth age group (51.7%) (P = .004, P = .008, and P = .04, respectively). The 2-year overall survival rates were 63.7% and 66.8% in the first 2 age groups, which were higher than the rates in the last 2 age groups (34.2% and 14.8%) (P = .02, P = .03, P < .001, and P < .001, respectively). The 1-year cumulative incidences of nonrelapse mortality were 10.2%, 0%, 3.4%, and 26.0% in the 4 age groups and 8.1% in all patients. The median times to neutrophil and platelet recovery were 12 days and 14 days after induction chemotherapy, respectively. Five patients had full or mixed donor engraftment, and 30.8% (8 of 26) of patients demonstrated donor microchimerism. Two patients (1.1%) developed severe acute graft-vs-host disease. Conclusions and Relevance Microtransplant achieved a high complete remission rate in AML patients aged 60 to 85 years and higher 1-year overall survival in those aged 60 to 74 years.

Therapy-related, mixed-lineage leukaemia translocation-positive, monoblastic myeloid sarcoma of the uterus

Myeloid sarcomas are tumour masses of myeloid leukaemic cells at extramedullary sites. These tumours can, on occasion, occur without concurrent or antecedent leukaemia. Myeloid sarcomas have been described at unusual locations including the female genital tract. An unusual case of therapy-related acute myeloid leukaemia (t-AML) presenting as isolated monoblastic myeloid sarcoma of the uterus in a patient who had received adjuvant chemotherapy for breast cancer is presented. Fluorescence in situ hybridisation analysis performed on paraffin-wax-embedded tumour tissue revealed a mixed-lineage leukaemia (MLL) gene rearrangement, supporting the association of this malignancy with prior chemotherapy. This case illustrates that t-AML can rarely present as isolated extramedullary tumours, and the detection of specific chromosomal abnormalities in these myeloid sarcomas can be useful for risk assessment and guiding definitive therapy.

A phase II trial of pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone (DR-COP) in aggressive B-cell non-Hodgkin's lymphoma

6688 Background: Pegylated liposomal doxorubicin (Doxil/Caelyx) has an improved pharmacokinetic profile over conventional doxorubicin with decreased cardiotoxicity. We replaced conventional doxorubicin with Doxil in the R-CHOP regimen (DR-COP) to define the efficacy and safety of this regimen. METHODS Patients (pts) received Doxil, 40 mg/m2, cyclophosphamide, 750 mg/m2, vincristine, 2.0 mg, all given IV on day 1; prednisone, 100 mg was given orally on days 1-5. Rituxan, 375 mg/m2 IV day 1 was added to the regimen starting cycle 2. Chemotherapy cycles were repeated every 21 days and given until 2 cycles beyond complete remission for a maximum of 8 cycles. RESULTS To date, 19 pts have been enrolled and included in this analysis. Baseline demographics: median age 51 years (range 20-74); all pts were CD20+ positive with diffuse large cell lymphoma in 16, high grade not otherwise specified in 2, and follicular grade 3 in 1. 16 (84%) pts had stage IV disease. 7 (37%) had elevated serum LDH levels. Ten pts (53%) had an intermediate or high risk IPI score. In total, 15 pts are evaluable for response: 12 complete or clinical complete remissions (80%) have been documented; 3 pts had partial remission with one proceeding to stem cell transplant. After a median follow-up of 7.7 months (up to 10.9 months), one CR patient relapsed after 3 months. Toxicities have been primarily hematologic with transient grade 3 or 4 neutropenia in 13 (68%) pts. Grade 3 anemia and thrombocytopenia were reported in 1 patient each. Delays in therapy or Doxil dose reductions were required in 5 pts (26%) for grade 2 or 3 hand-foot syndrome (HFS) and in 4 others (21%) for grade 2 mucositis. Other non-hematologic toxicities were grade 1 or 2 in severity. CONCLUSIONS Preliminary results show that pegylated liposomal doxorubicin (Doxil) used as replacement for conventional doxorubicin in the R-CHOP regimen is active in aggressive NHL. The regimen is well tolerated with the incidence of HFS and mucositis consistent with single agent Doxil at this dose and schedule. Accrual is ongoing and updated results will be presented. [Table: see text].