Ann Mohrbacher - Academia.edu (original) (raw)

Papers by Ann Mohrbacher

Cancer Chemotherapy and Pharmacology, Mar 20, 2010

Hematological Oncology, 2019

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor,... more Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed.

Hematological Oncology, 2019

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor,... more Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed.

Blood, 2008

Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a ... more Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a survival benefit in patients with high-risk myelodysplastic syndrome and is under investigation in other cancers. The purpose of this study was to determine the optimal dose and route of administration for azacitidine to inhibit DNA methylation in patients with hematologic malignancies. Eligibility included patients with hematologic malignancy who provided informed consent. Enrollment criteria varied depending on the type of cancer. Patients were enrolled into 5 escalating dose levels for the first course of therapy (25mg, 50mg, 75mg, 100mg or 150mg IV per m2 per day for 5 days). On day 28 all patients received 75mg/m2/day IV for 5 days. For course 3 patients received 75mg/m2/day SQ × 5 days. Beyond course 3 patients received 75mg/m2/day either SQ or IV × 5 days every 4 weeks. Peripheral blood was collected on days 1, 3 and 5 for each course and LINE1 DNA methylation was measured using b...

Blood, 2016

Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are dia... more Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are diagnostically challenging and carry a poor prognosis. Incidence is notably higher in Asian countries as compared to North America and Europe. South Americans have an incidence similar to Asian countries though less well described. In this study we reviewed the incidence and outcomes of NK/T NHL in the US with a specific focus on patient race/ethnicity. Methods: Surveillance, Epidemiology and End Results (SEER) database was used to examine the standardized incidence rates (SIR) of NK/T cell NHL among adult (≥18 yrs) patients diagnosed between 1992-2013. Mutually exclusive race/ethnicity categories were: African-Americans (AA), Asians/Pacific Islanders (API), Hispanic whites (HW) and Non-Hispanic whites (NHW). Cases that received a diagnosis at death certificate/autopsy, no follow-up records, or lacking age at diagnosis, sex, or race/ethnicity documentation were excluded. Age adjusted incide...

Blood, 2013

Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factor... more Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of ag...

Blood, 2009

4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly impr... more 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagon...

Blood, 1993

The present studies have examined the effects of mitogens on induction of early response gene exp... more The present studies have examined the effects of mitogens on induction of early response gene expression in normal peripheral blood T and Jurkat cells. Pokeweed mitogen (PWM) or anti-CD3 significantly increases c-jun messenger RNA (mRNA) levels in T cells. This transient PWM-related increase in c-jun transcripts is maximal after 15 to 30 minutes of exposure of T cells to PWM. PWM induces c-jun gene expression in a concentration-dependent manner. Moreover, PWM similarly induces expression of other genes coding for leucine zipper transcription factors, ie, jun-B and c-fos. Nuclear run on assays demonstrate that PWM treatment is associated with an increased rate of c-jun gene transcription. Transient expression assays with c-jun promoter fragments linked to the chloramphenicol acetyltransferase gene suggest that the PWM-induced increase in transcription is mediated by the AP-1 transcription factor complex. Moreover, treatment of T cells with actinomycin D to block further transcription...

Blood, 2010

4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an imp... more 4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic modality for MM patients. Traditionally high-dose single agent melphalan (200 mg/m2; Mel-200) has been used as the conditioning regimen prior to ASCT for MM. We investigated the combination regimen of BCNU, etoposide and melphalan (BEM) in this setting at our center. Methods: All patients who had undergone ASCT for MM utilizing BEM conditioning regimen at Norris Cancer Center, University of Southern California, Los Angeles were eligible. BEM consisted of BCNU 12 mg/kg (actual body weight or ideal body weight whichever was lower) iv on day -5, etoposide 60 mg/Kg iv on day -3, and melphalan 140 mg/m2 iv on day -1, prior to stem cell reinfusion on day 0. Overall survival (OS) was defined as time from MM diagnosis to death, or in patients still alive, the date of last follow-up. Progression-free survival (PFS) was defined as time from ASCT to date of relapse, or in patient...

Blood, 2010

3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surfa... more 3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods: The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on day...

Blood, 2006

Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of... more Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in wh...

Blood, 2016

Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM)... more Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM) than persons of European ancestry (EA). Like other B-cell malignancies, genome-wide association scans (GWAS) have identified MM risk variants in the HLA region in persons of EA. We conducted a case-control analysis with data from the National Marrow Donor Program (NMDP)1comprising MM patients typed for bone marrow transplant to donor controls matched by race-ethnicity, and found associations between specific HLA alleles/haplotypes and MM risk that varied by race and ethnicity. To confirm our results and identify additional novel signals, we have now investigated associations between HLA alleles and haplotypes and MM risk in the African American Multiple Myeloma Study (AAMMS) Cohort. Methods: The source of subjects was the AAMMS, in which AA MM patients were identified from 10 cancer centers and 4 Surveillance, Epidemiology and End-Results (SEER) Program cancer registries in order to ide...

Journal of Clinical Oncology, 2015

8573 Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Mole... more 8573 Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Molecule F7 (SLAMF7), kills myeloma cells with minimal effects on normal tissue. Elo showed enhanced activity when combined with Btz in a preclinical myeloma model, (van Rhee F, et al. Mol Cancer Ther 2009;8:2616–24) and encouraging clinical activity in a Ph 1 study (Jakubowiak A, et al. J Clin Oncol 2012;30:1960–65). This Ph 2 open-label study (NCT01478048, CA204-009) investigated the efficacy and safety of Elo + Btz/dex (Bd) in pts with RRMM. Methods: Pts with RRMM, 1–3 prior therapies, were given Elo + Bd (EBd) or Bd in 21-d (Cycles 1–8) or 28-d cycles (9+) to disease progression/unacceptable toxicity. Elo (10 mg/kg IV): wkly Cycles 1–2, D1+11 Cycles 3–8, then D1+15; Btz (1.3 mg/m2 IV/SC): D1, 4, 8+11 Cycles 1–8, then D1, 8+15; dex 20 mg non-Elo days, 28 mg PO + 8 mg IV Elo days. Primary endpoint: PFS (ITT population). A 2-sided 0.30 significance level was specified (80% power, 103 events) to detect a hazard ra...

Journal of Clinical Oncology, 2004

6509 Background: Pegylated liposomal doxorubicin (Doxil/Caelyx) was used as a replacement for con... more 6509 Background: Pegylated liposomal doxorubicin (Doxil/Caelyx) was used as a replacement for conventional doxorubicin in the VAd regimen to improve the safety profile. Methods: This multicenter randomized trial compared the efficacy and safety of DVd (pegylated liposomal doxorubicin 40 mg/m2 and vincristine 1.4 mg/m2 [max 2.0 mg/m2] IV on Day 1, and reduced-dose dexamethasone 40 mg PO on Days 1–4) with VAd (vincristine 0.4 mg/day and conventional doxorubicin 9 mg/m2/day by continuous IV infusion on Days 1–4 and dexamethasone 40 mg PO on Days 1–4) in patients with newly diagnosed multiple myeloma. Treatment was repeated every 4 weeks until transplantation, disease progression, stable plateau disease, or unacceptable toxicity. Primary endpoints were objective response and clinical benefit (defined as reduced hospitalization due to adverse events, documented sepsis, antibiotic use, and grade 3/4 neutropenia or neutropenic fever). Results: Patient demographics were similar for both groups. Safety and efficac...

JAMA Oncology, 2017

; for the Microtransplantation Interest Group IMPORTANCE The outcome of older patients with acute... more ; for 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.

Journal of Clinical Oncology, 2005

6714 Background: Bortezomib is a highly active agent in multiple myeloma. Advanced stages of mult... more 6714 Background: Bortezomib is a highly active agent in multiple myeloma. Advanced stages of multiple myeloma are freqeuntly associated with progressive renal failure. We report here 6 cases of acute advanced deterioration of renal function on prior renal insuficiency in chronic MM patients, with complete or near complete reversal of severe renal dysfunction after treatment with Velcade and Dexamethasone. Methods: Pts received Velcade 1.0 mg/m2/d IV d1,4,8,11 and Dexamethasone 20 mg IV d1,4,8,11. Results: Rapid reversal of acute deterioration of renal dysunction was demonstrated after treatment with Velcade and Dexamethasone in this retrospective review of patient cases. Improvement of renal function was generally evident quickly, often less than 2 weeks, earlier than expected from general myeloma tumor response. A review of a trial of treatment with Velcade where Dexamethasone was added in later cycles may address possible evidence of synergy of Velcade and dexamethasone in reversal of renal dysfunction....

European Journal of Haematology, 2015

Despite having been long regarded as too toxic for adult patients, pediatric‐like regimens contai... more 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 ...

Medical Oncology, 2013

Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed... more Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed/refractory acute lymphoblastic leukemia (ALL), and this represents a major barrier for performing allogeneic hematopoietic stem cell transplant (HSCT), the only potentially curative treatment. We conducted in adults with first relapse of ALL, a prospective clinical trial with intensive regimen derived from the pediatric Berlin-Frankfurt-Muenster-85 protocol, with addition of a continuous infusional multi-agent chemotherapy in phase II induction followed by consolidation with alternating monthly cycles. Objectives of this study included CR rate, leukemia-free survival (LFS) and toxicity of the regimen in adults. We report the outcome of 19 patients (19-51 years of age) treated prospectively on the study, as well as a subsequent cohort of 31 patients (18-53 years of age) treated off the study. Thirteen of 19 (68%) patients from the initial prospective study achieved CR, and the median overall survival (OS) of these 13 CR patients was 10.3 months. The median OS and LFS of all 19 patients were 5.6 and 4.3 months, respectively. The regimen was well tolerated, and no grade 4 non-hematological toxicity was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16 (52%) achieved CR. After including all 50 patients, the CR rate was 58%. The regimen used in this trial appears to be feasible and effective salvage therapy option for adult patients younger than age 55 with relapsed ALL, produced a high CR rate and could facilitate subsequent allogeneic HSCT.

Cancer Chemotherapy and Pharmacology, Mar 20, 2010

Hematological Oncology, 2019

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor,... more Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed.

Hematological Oncology, 2019

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor,... more Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed.

Blood, 2008

Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a ... more Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a survival benefit in patients with high-risk myelodysplastic syndrome and is under investigation in other cancers. The purpose of this study was to determine the optimal dose and route of administration for azacitidine to inhibit DNA methylation in patients with hematologic malignancies. Eligibility included patients with hematologic malignancy who provided informed consent. Enrollment criteria varied depending on the type of cancer. Patients were enrolled into 5 escalating dose levels for the first course of therapy (25mg, 50mg, 75mg, 100mg or 150mg IV per m2 per day for 5 days). On day 28 all patients received 75mg/m2/day IV for 5 days. For course 3 patients received 75mg/m2/day SQ × 5 days. Beyond course 3 patients received 75mg/m2/day either SQ or IV × 5 days every 4 weeks. Peripheral blood was collected on days 1, 3 and 5 for each course and LINE1 DNA methylation was measured using b...

Blood, 2016

Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are dia... more Background: NK/T cell non-Hodgkin lymphomas (NK/T NHL) are rare high-grade lymphomas that are diagnostically challenging and carry a poor prognosis. Incidence is notably higher in Asian countries as compared to North America and Europe. South Americans have an incidence similar to Asian countries though less well described. In this study we reviewed the incidence and outcomes of NK/T NHL in the US with a specific focus on patient race/ethnicity. Methods: Surveillance, Epidemiology and End Results (SEER) database was used to examine the standardized incidence rates (SIR) of NK/T cell NHL among adult (≥18 yrs) patients diagnosed between 1992-2013. Mutually exclusive race/ethnicity categories were: African-Americans (AA), Asians/Pacific Islanders (API), Hispanic whites (HW) and Non-Hispanic whites (NHW). Cases that received a diagnosis at death certificate/autopsy, no follow-up records, or lacking age at diagnosis, sex, or race/ethnicity documentation were excluded. Age adjusted incide...

Blood, 2013

Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factor... more Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of ag...

Blood, 2009

4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly impr... more 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagon...

Blood, 1993

The present studies have examined the effects of mitogens on induction of early response gene exp... more The present studies have examined the effects of mitogens on induction of early response gene expression in normal peripheral blood T and Jurkat cells. Pokeweed mitogen (PWM) or anti-CD3 significantly increases c-jun messenger RNA (mRNA) levels in T cells. This transient PWM-related increase in c-jun transcripts is maximal after 15 to 30 minutes of exposure of T cells to PWM. PWM induces c-jun gene expression in a concentration-dependent manner. Moreover, PWM similarly induces expression of other genes coding for leucine zipper transcription factors, ie, jun-B and c-fos. Nuclear run on assays demonstrate that PWM treatment is associated with an increased rate of c-jun gene transcription. Transient expression assays with c-jun promoter fragments linked to the chloramphenicol acetyltransferase gene suggest that the PWM-induced increase in transcription is mediated by the AP-1 transcription factor complex. Moreover, treatment of T cells with actinomycin D to block further transcription...

Blood, 2010

4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an imp... more 4587 Background: High-dose chemotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic modality for MM patients. Traditionally high-dose single agent melphalan (200 mg/m2; Mel-200) has been used as the conditioning regimen prior to ASCT for MM. We investigated the combination regimen of BCNU, etoposide and melphalan (BEM) in this setting at our center. Methods: All patients who had undergone ASCT for MM utilizing BEM conditioning regimen at Norris Cancer Center, University of Southern California, Los Angeles were eligible. BEM consisted of BCNU 12 mg/kg (actual body weight or ideal body weight whichever was lower) iv on day -5, etoposide 60 mg/Kg iv on day -3, and melphalan 140 mg/m2 iv on day -1, prior to stem cell reinfusion on day 0. Overall survival (OS) was defined as time from MM diagnosis to death, or in patients still alive, the date of last follow-up. Progression-free survival (PFS) was defined as time from ASCT to date of relapse, or in patient...

Blood, 2010

3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surfa... more 3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods: The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on day...

Blood, 2006

Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of... more Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in wh...

Blood, 2016

Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM)... more Background: Persons of African ancestry (AA) have a 2-3-fold higher risk of multiple myeloma (MM) than persons of European ancestry (EA). Like other B-cell malignancies, genome-wide association scans (GWAS) have identified MM risk variants in the HLA region in persons of EA. We conducted a case-control analysis with data from the National Marrow Donor Program (NMDP)1comprising MM patients typed for bone marrow transplant to donor controls matched by race-ethnicity, and found associations between specific HLA alleles/haplotypes and MM risk that varied by race and ethnicity. To confirm our results and identify additional novel signals, we have now investigated associations between HLA alleles and haplotypes and MM risk in the African American Multiple Myeloma Study (AAMMS) Cohort. Methods: The source of subjects was the AAMMS, in which AA MM patients were identified from 10 cancer centers and 4 Surveillance, Epidemiology and End-Results (SEER) Program cancer registries in order to ide...

Journal of Clinical Oncology, 2015

8573 Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Mole... more 8573 Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Molecule F7 (SLAMF7), kills myeloma cells with minimal effects on normal tissue. Elo showed enhanced activity when combined with Btz in a preclinical myeloma model, (van Rhee F, et al. Mol Cancer Ther 2009;8:2616–24) and encouraging clinical activity in a Ph 1 study (Jakubowiak A, et al. J Clin Oncol 2012;30:1960–65). This Ph 2 open-label study (NCT01478048, CA204-009) investigated the efficacy and safety of Elo + Btz/dex (Bd) in pts with RRMM. Methods: Pts with RRMM, 1–3 prior therapies, were given Elo + Bd (EBd) or Bd in 21-d (Cycles 1–8) or 28-d cycles (9+) to disease progression/unacceptable toxicity. Elo (10 mg/kg IV): wkly Cycles 1–2, D1+11 Cycles 3–8, then D1+15; Btz (1.3 mg/m2 IV/SC): D1, 4, 8+11 Cycles 1–8, then D1, 8+15; dex 20 mg non-Elo days, 28 mg PO + 8 mg IV Elo days. Primary endpoint: PFS (ITT population). A 2-sided 0.30 significance level was specified (80% power, 103 events) to detect a hazard ra...

Journal of Clinical Oncology, 2004

6509 Background: Pegylated liposomal doxorubicin (Doxil/Caelyx) was used as a replacement for con... more 6509 Background: Pegylated liposomal doxorubicin (Doxil/Caelyx) was used as a replacement for conventional doxorubicin in the VAd regimen to improve the safety profile. Methods: This multicenter randomized trial compared the efficacy and safety of DVd (pegylated liposomal doxorubicin 40 mg/m2 and vincristine 1.4 mg/m2 [max 2.0 mg/m2] IV on Day 1, and reduced-dose dexamethasone 40 mg PO on Days 1–4) with VAd (vincristine 0.4 mg/day and conventional doxorubicin 9 mg/m2/day by continuous IV infusion on Days 1–4 and dexamethasone 40 mg PO on Days 1–4) in patients with newly diagnosed multiple myeloma. Treatment was repeated every 4 weeks until transplantation, disease progression, stable plateau disease, or unacceptable toxicity. Primary endpoints were objective response and clinical benefit (defined as reduced hospitalization due to adverse events, documented sepsis, antibiotic use, and grade 3/4 neutropenia or neutropenic fever). Results: Patient demographics were similar for both groups. Safety and efficac...

JAMA Oncology, 2017

; for the Microtransplantation Interest Group IMPORTANCE The outcome of older patients with acute... more ; for 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.

Journal of Clinical Oncology, 2005

6714 Background: Bortezomib is a highly active agent in multiple myeloma. Advanced stages of mult... more 6714 Background: Bortezomib is a highly active agent in multiple myeloma. Advanced stages of multiple myeloma are freqeuntly associated with progressive renal failure. We report here 6 cases of acute advanced deterioration of renal function on prior renal insuficiency in chronic MM patients, with complete or near complete reversal of severe renal dysfunction after treatment with Velcade and Dexamethasone. Methods: Pts received Velcade 1.0 mg/m2/d IV d1,4,8,11 and Dexamethasone 20 mg IV d1,4,8,11. Results: Rapid reversal of acute deterioration of renal dysunction was demonstrated after treatment with Velcade and Dexamethasone in this retrospective review of patient cases. Improvement of renal function was generally evident quickly, often less than 2 weeks, earlier than expected from general myeloma tumor response. A review of a trial of treatment with Velcade where Dexamethasone was added in later cycles may address possible evidence of synergy of Velcade and dexamethasone in reversal of renal dysfunction....

European Journal of Haematology, 2015

Despite having been long regarded as too toxic for adult patients, pediatric‐like regimens contai... more 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 ...

Medical Oncology, 2013

Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed... more Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed/refractory acute lymphoblastic leukemia (ALL), and this represents a major barrier for performing allogeneic hematopoietic stem cell transplant (HSCT), the only potentially curative treatment. We conducted in adults with first relapse of ALL, a prospective clinical trial with intensive regimen derived from the pediatric Berlin-Frankfurt-Muenster-85 protocol, with addition of a continuous infusional multi-agent chemotherapy in phase II induction followed by consolidation with alternating monthly cycles. Objectives of this study included CR rate, leukemia-free survival (LFS) and toxicity of the regimen in adults. We report the outcome of 19 patients (19-51 years of age) treated prospectively on the study, as well as a subsequent cohort of 31 patients (18-53 years of age) treated off the study. Thirteen of 19 (68%) patients from the initial prospective study achieved CR, and the median overall survival (OS) of these 13 CR patients was 10.3 months. The median OS and LFS of all 19 patients were 5.6 and 4.3 months, respectively. The regimen was well tolerated, and no grade 4 non-hematological toxicity was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16 (52%) achieved CR. After including all 50 patients, the CR rate was 58%. The regimen used in this trial appears to be feasible and effective salvage therapy option for adult patients younger than age 55 with relapsed ALL, produced a high CR rate and could facilitate subsequent allogeneic HSCT.