Relapsed non-Hodgkin Lymphoma Research Articles

Results of a phase I study of bendamustine in combination with ofatumumab, carboplatin, and etoposide (BOCE) for refractory or relapsed aggressive B-cell non-Hodgkin lymphomas (NHL).

8556 Background: No salvage regimen has shown clear superiority in relapsed NHL. Bendamustine has single agent activity in relapsed aggressive NHL. We conducted a phase I trial using a novel RICE-like salvage regimen in which ofatumumab was substituted for rituximab and bendamustine replaced ifosfamide, combined with carboplatin and etoposide (BOCE) Methods: Patients (pts) with relapsed or refractory aggressive B NHL were eligible. The design was a standard 3+3 design using escalating doses of bendamustine [70, 90, and 120 mg/m2 D1-2] with ofatumumab (cycle 1: 300 mg D1, 1000 mg D3, cycle 2 and 3: 1000 mg D1), carboplatin AUC 5 D2 and etoposide 100mg/m2 D1-3. Results: Eleven pts were enrolled (7M/4F). Median age was 62 (range 53-75), 5 pts (45%) had diffuse large B NHL, 4 pts (36%) had grade 3 follicular NHL, 1 pt (9%) had mantle cell NHL, and 1 pt (9%) had transformed CLL. Five pts (46%) had refractory disease and 6 pts (56%) had relapsed disease. All pts with refractory disease were refractory to rituxi...

Immunologic and Clinical Responses To a CD20-Targeted Immunocytokine, DI-Leu16-IL2, In Relapsed Non-Hodgkin Lymphoma

BackgroundTumor-targeted antibody-cytokine fusion proteins, known as immunocytokines (ICKs) have potent antitumor activity in several preclinical tumor models. We have engineered an anti-CD20-interleukin 2 (IL-2) ICK based on the Leu16 anti-CD20 antibody with de-immunized variable (V) region and junction between the heavy (H) chain constant region and IL-2 (DI-Leu16-IL2). In-vitro studies of DI-Leu16-IL2 have demonstrated CD20 targeting, IL2 bioactivities, and antibody-dependent cell-mediated cytotoxicity (ADCC) functions. In a SCID mouse model, DI-Leu16-IL2 showed superior anti-lymphoma effects over rituximab or rituximab combined with systemic IL-2. MethodsWe have initiated a pilot trial of DI-Leu16-IL20 in CD20+ B-cell non-Hodgkin lymphoma (NHL) under an IRB-approved protocol (clinicaltrials.gov: NCT00720135). A total of 7 patients have been treated with DI-Leu16-IL20 at 0.5mg/m2. The first 2 cases received DI-Leu16-IL2 by intravenous infusion on days 2, 4 and 23, 25 after peripheral B cell depletion with low-dose rituximab (50mg/m2) on days 1 and 22. Five remaining patients received DI-Leu16-IL2 weekly for 4 weeks (days 2, 9, 16, 23) after B cell depletion with low-dose rituximab on days 1, 8, 15, and/or 22 as necessary, based on serum rituximab levels. Clinical ResponsesThe treatment has been generally well tolerated with the majority of adverse events (AE) grade 1 or 2. Non-DLT grade 3 AE included one case of hyperglycemia, infection (herpes zoster), and prolonged QTc. One patient developed grade 3 hyponatremia, which was the only DLT in the study to date. One patient with diffuse large B cell NHL of the lower extremity achieved a CR after 2 cycles (significant PR after cycle 1; Figure 1). Another patient showed a temporal increase in FDG uptake on PET after cycle 1, which decreased after cycle 2 in 2 of the 3 responding lymph nodes, suggesting a local immunologic reaction with corresponding FDG uptake (immune-mediated FDG flare). A lymph node biopsy demonstrated a dense infiltration of T cells. One patient who had her residual tumor biopsied after DI-Leu16-IL2 treatment demonstrated loss of CD20 expression.Pre-ICK B Cell Depletion and Pharmacologic Data: We have successfully maintained minimal or absent peripheral blood B cells, with a level-guided dosing of low-dose rituximab. The Cmax ranged between 75 and 125 ng/ml following each infusion of DI-Leu16-IL2. The half life was 6-8 hours and did not change significantly between doses. We have detected no anti-DI-Leu16-IL2 antibodies in any of the 7 patients treated on this protocol. [Display omitted] Immunologic ResponsesDI-Leu16-IL2 was highly immunologically active. There was a significant increase in local infiltrating T cells (predominantly CD8 T cells) in lymph node samples taken after DI-Leu16-IL2 in 3 of the 4 cases whose samples were available. Soluble IL2 receptor levels spiked with each DI-Leu16-IL2 infusion, up to 3 times above baseline. Among the cytokines and chemokines we evaluated using the Luminex platform, IL-5, IL-7, IL-10, IP10, IL-15, and IFN-gamma demonstrated high spikes (>2-fold increase) within 12 hours from each DI-Leu16-IL2 infusion, while IL-1, IL-12, MIG, TNF-alpha, IFN-alpha, and GCSF levels had a lesser degree of spikes (<2-fold increase). The data on the CR patient seem to show higher peak levels of IL15, IL7, and IP10, while MCP1, IL5, IL10, and MCP appeared lower compared with others. Flow cytometry-based cellular analyses showed no significant increase in regulatory T cells or myeloid-derived suppressor cells. Peripheral blood T cells were analyzed for TCR CDR3 sequence, and demonstrated oligoclonal T cell expansions, suggestive of antigen-driven T cell expansion. ConclusionThis study demonstrated the clinical and immunologic data consistent with a proof-of-principle that DI-Leu16-IL2 is capable of inducing both local and systemic immune responses at a dose 0.5mg/m2, and was associated with a CR in a patient who had highly refractory NHL. A multi-center phase I trial of subcutaneously administered DI-Leu16-IL2 is currently underway. Disclosures:Gillies: Provenance Biopharmaceuticals Corp (employment and equity ownership), Alopexx Oncology (Consultancy) : Consultancy, Employment, Equity Ownership.

Management of Relapses After Hematopoietic Cell Transplantation in T-Cell Non-Hodgkin Lymphomas

T-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies that represent 10%-15% of all NHLs. The prognosis of relapsed T-cell NHL is poor, especially for those relapsing after an autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT). Disease relapse post auto-HCT is best managed on a clinical trial. In the absence of an investigational protocol, the choice of salvage therapies should take into account patient performance status, eligibility for an allo-HCT, and surface CD30 expression. CD30-directed therapies or aggressive salvage regimens can be used as a bridge to allo-HCT in medically fit patients. In the elderly or more infirm patients, single-agent therapies could be offered, aiming at palliation. Similarly, relapse after an allo-HCT is not uncommon and is a real challenge. Reduction in ongoing immune suppression or donor lymphocyte infusion are often considered in this setting to augment graft-versus-lymphoma (GVL) effects and can occasionally provide durable disease control. Clinical trials designed to investigate novel therapeutic agents with immunomodulatory properties to augment GVL effects (eg, histone deacetylase [HDAC] inhibitors, proteasome inhibitor, lenalidomide) or targeted therapies (eg, aurora A kinase inhibitors, anaplastic lymphoma kinase [ALK] inhibitors) are sorely needed to improve the dismal outcomes of T-cell NHL relapsing after an allo-HCT.

Vincristine Sulfate Liposome Injection (Marqibo®) and Rituximab For Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma Or Mantle Cell Lymphoma In Need Of Palliative Therapy

BackgroundDespite advances in combination immuno-chemotherapy and hematopoietic cell transplant (HCT) and improvements in long-term disease-free survival and cure rates for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell aggressive non-Hodgkin lymphomas (NHL), nearly half of patients will fail therapy and require disease palliation. Vincristine sulfate liposome injection (VSLI; Marqibo®) was developed to optimize vincristine (VCR) pharmacokinetics, dose-intensification, and target-tissue delivery. VSLI is active in relapsed and refractory NHL as a single-agent and in untreated aggressive NHL as replacement for non-liposomal VCR in CHOP±R combination chemotherapy. Because of a primarily non-hematologic toxicity profile, VSLI may be useful in patients considered unable to tolerate myelosuppressive therapies. MethodsTwenty-two patients with heavily pre-treated, relapsed and refractory CD20+ DLBCL or mantle cell lymphoma (MCL) were treated with combination therapy consisting of VSLI 2.0 mg/m2, without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m2. Objective response rate (ORR), consisting of achievement of complete response (CR) or partial response (PR), was the primary efficacy endpoint. Secondary efficacy endpoints included response duration, time to progression (TTP), and overall survival (OS). Safety variables included adverse events and neurologic assessments. ResultsThe ORR was 59% (13/22) including CR in 6 (27%) patients and PR in 7 (32%) patients. Stable disease was documented in an additional 3 (14%) patients. Median response duration, TTP and OS were 147 days, 121 days and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. There were no toxicity-associated deaths during the study period. Treatment-related Grade 3 peripheral neuropathy and constipation were reported in 4 patients and 1 patient, respectively. There was no Grade 4 neuropathy. Grade 3 febrile neutropenia developed in 2 patients. ConclusionHigh dose VSLI plus rituximab, as palliative therapy for heavily pre-treated, predominantly older, patients with advanced, relapsed and refractory DLBCL and MCL, was generally well-tolerated and resulted in a meaningful ORR of 59%, median response duration of approximately 5 months, and median OS of almost 11 months. The toxicity profile of this combination was predictable and manageable with limited hematologic toxicity. Despite near universal prior VCR exposure (96%) and doses of VSLI normally unachievable with non-liposomal VCR, peripheral neuropathy and constipation incidences were modest. Older patients, those who are multiply relapsed, and others who are unlikely to tolerate prolonged periods of myelosuppression are often considered best suited for palliative therapy intended to prolong and maintain quality life. VSLI combined with rituximab may provide such palliation. Disclosures:Off Label Use: Marqibo is currently approved for the treatment of adults with Ph- relapsed/refractory ALL. Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Limited Utility of Surveillance Imaging for Detecting Disease Relapse in Patients With Non-Hodgkin Lymphoma in First Complete Remission

Surveillance imaging with computed tomography (CT) or positron emission tomography with CT (PET/CT) is commonly used in practice in patients with non-Hodgkin lymphoma (NHL) who are in remission after front-line therapies. We aimed to determine the utility of routine imaging for detecting first relapse in patients with NHL in complete remission (CR) after first-line therapies. We retrospectively analyzed patients with NHL who achieved CR after first-line therapies and then subsequently had disease relapse. We evaluated whether the relapse was detected solely by surveillance CT or PET/CT or by patient-reported symptoms or physical examination findings, or both. Subgroup analysis was performed on baseline histologic type (indolent vs. aggressive NHL). Data were also collected to determine the cost of surveillance PET/CT and the number of additional diagnostic imaging procedures, invasive procedures, and iatrogenic complications directly resulting from an abnormality detected on a surveillance scan. One hundred sixty-three patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. The majority of the relapses were detected by patient-reported symptoms or physical examination, or both, as opposed to surveillance imaging (77.9% [n = 127] vs. 22.1% [n = 36]; P < .0001). There was no overall survival difference between the 2 groups (P = .66). Patient-reported symptoms led to the detection of the majority of relapses in aggressive (85.7% [n = 72] vs. 14.3% [n = 12]; P < .0001) as well as indolent NHL (69.6% [n = 55] vs. 30.4% [n = 24]; P = .0007). Surveillance PET/CT contributed to more than 75% of follow-up health care costs in the first 2 years of monitoring for relapse. The surveillance imaging group had 1 reported case of iatrogenic pneumothorax. Our retrospective analysis suggests that there is a limited role for surveillance imaging by CT or PET/CT in detecting first relapse in NHL. There was no difference in survival outcomes between the 2 groups in our study.

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy.

Limited utility of surveillance imaging for detection of relapse in non-Hodgkin lymphoma.

8557 Background: Surveillance imaging with computerized tomography (CT) and positron emission tomography with CT (PET/CT) scans during follow-up after first-line therapies in patients with non-Hodgkin lymphoma (NHL) is commonly used in practice. However, most guidelines do not recommend surveillance imaging. We aimed to determine the value of routine imaging for the detection of first relapse in NHL patients in complete remission (CR) after first-line therapies. Methods: We retrospectively analyzed NHL patients referred to our center, who achieved CR after first-line therapies and subsequently relapsed. We evaluated whether the relapse was detected solely by routine CT or PET/CT or by patient-reported symptoms. Subgroup analysis was performed according to baseline histology (indolent vs. aggressive NHL). Data were also collected to determine the number of additional imaging, number of false positive scans, invasive procedures and iatrogenic complications, directly resulting from an abnormality detected on surveillance imaging. Results: Seventy-seven patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. Majority of the relapses were detected by patient-reported symptoms as opposed to surveillance imaging (79.2% (n=61) vs. 20.8% (n=16); p&lt;0.0001). There was no overall survival difference between the two groups (p=0.08). Patient-reported symptoms led to the detection of majority of relapses in aggressive (86.4% (n=45) vs. 13.6% (n=6); p&lt;0.0001) and indolent NHL (69.7% (n=32) vs. 30.3% (n=10); p=0.037). There were greater number of scans done after a suspected relapse in the imaging versus symptoms group (1.94 versus 0.97; p=0.0004). Surveillance imaging led to 2 false positive scans/invasive procedures with one case of iatrogenic pneumothorax. Conclusions: Our limited retrospective analysis suggests that there is a limited role of surveillance imaging by CT or PET/CT for the detection of relapse in patients with NHL. There was no difference in survival outcome in our study between the two groups.

Trends in Use of and Survival after Autologous Hematopoietic Cell Transplantation in North America, 1995-2005: Significant Improvement in Survival for Lymphoma and Myeloma during a Period of Increasing Recipient Age

Autologous hematopoietic cell transplantation (auto-HCT) is performed to treat relapsed and recurrent malignant disorders and as part of initial therapy for selected malignancies. This study evaluated changes in use, techniques, and survival in a population-based cohort of 68,404 patients who underwent first auto-HCT in a US or Canadian center between 1994 and 2005 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The mean annual number of auto-HCTs performed was highest during 1996-1999 (6948), and decreased subsequently 2000-2003 (4783), owing mainly to fewer auto-HCTs done to treat breast cancer. However, the mean annual number of auto-HCTs increased from 5278 annually in 1994-1995 to 5459 annually in 2004-2005, reflecting increased use for multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Despite an increase in the median recipient age from 44 to 53 years, there has been a significant improvement in overall survival (OS) from 1994 to 2005 in patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma (day +100 OS, from 85% to 96%; 1-year OS, from 68% to 80%; P < .001) and chemotherapy-sensitive multiple myeloma (day +100 OS, from 96% to 98%; 1-year OS, from 83% to 92%; P < .001). This improvement in OS was most pronounced in middle-aged (>40 years) and older (>60 years) individuals.

Foliculitis necrotizante herpética

Herpes folliculitis is a rare manifestation of herpes virus infection. It usually represents a diagnostic challenge, due to the absence of characteristic skin manifestations such as vesicles or pustules. The reported cases are mainly associated with varicella zoster virus (VZV) and less commonly with herpes simplex viruses (HSV-1 y HSV-2). We report a 51-year-old male with a relapsing non-Hodgkin Lymphoma under chemotherapy, with history of extensive follicular lesions lasting one month. The pathologic study of the lesions was consistent with necrotizing herpes folliculitis. The patient was treated with Valacyclovir, achieving remission of the lesions. The appearance of folliculitis, especially in an immunocompromised patient, should raise the suspicion of herpes virus infection. Polymerase chain reaction may help to elucidate the diagnosis when pathologic findings are non-specific.

The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

AbstractAbstract 156 BackgroundBruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. MethodsAdult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). ResultsMedian age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%.Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator.One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held > 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached.In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. ConclusionsThe BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures:Advani:Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

The BCL-2-Specific BH3-Mimetic ABT-199 (GDC-0199) Is Active and Well-Tolerated in Patients with Relapsed Non-Hodgkin Lymphoma: Interim Results of a Phase I Study

AbstractAbstract 304 Background:BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki<0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods:This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3], 400 mg [n=4], and 600 mg [n=7]. Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results:To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy (>5cm). Most common AEs (experienced by >2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in >1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of >50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions:ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures:Roberts:Abbott: Research Funding; Genentech: Research Funding. Anderson:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kahl:Genentech: Consultancy, Research Funding; Abbott: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Yang:Abbott: Employment, own Abbott stock Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Seymour:Roche: Advisory board member, Advisory board member Other, Consultancy; Genentech: Advisory board member, Advisory board member Other, Consultancy.

Phase I Study of Intravenous PI3K Inhibitor Bay 80–6946: Preliminary Activity in Patients with Relapsed Non-Hodgkin Lymphoma (NHL) Treated in an MTD Expansion Cohort

AbstractAbstract 3704 Background:BAY 80–6946 is a potent and highly selective, reversible, pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor, with broad antitumor activity in a panel of preclinical models including both indolent and aggressive NHL. Even in the absence of PIK3CA mutations, the PI3 pathway has been demonstrated to be constitutively activated in the majority of B-cell lymphomas. BAY 80–6946 was more potent than CAL-101 in inhibiting the in vitro growth of a panel of leukemia/lymphoma cell lines. Methods:In a phase I dose escalation study, BAY 80–6946 was previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg (MTD) on days 1, 8 and 15 every 28 days (J Clin Oncol 29: 2011 suppl; abstr 3035). Additional patients were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected patient populations, including one expansion cohort in NHL. Based upon the beneficial clinical responses observed in 5 follicular lymphoma (FL) patients (J Clin Oncol 30: 2012 suppl; abstr 3019), the NHL cohort was expanded up to a total of 12 patients. Samples were collected for pharmacokinetic analyses. Exploratory analyses of changes in several plasma proteins, chosen with emphasis on B-cell homing/survival, were performed. Response was assessed using International Working Group response criteria, including 18FDG-PET. Results:To date, 9 NHL patients have been enrolled (FL, n=6, DLBCL, n=3). There were 5 females/4 males with a median age of 72 years (range, 40–84). Among these 9 patients, 5 (56%) had received 3 or more prior regimens. All have received prior Rituximab and 6/9 prior anthracycline and 4/9 prior Bendamustine. Eight patients were evaluable for safety and tolerability. The most frequently drug-related adverse events reported in >20% of the patients were hyperglycemia, nausea, diarrhea, anemia, mucositis, and fatigue. Interstitial pneumonitis was observed in 2 patients with FL. Both patients responded to corticosteroids and one continued on treatment at full dose without recurrence of the pneumonitis. The pharmacokinetic parameters of BAY 80–6946, including the Cmax and AUC, were consistent with those seen in solid tumour patients. Changes in the plasma levels of CXCL13 and BAFF were observed in subjects treated with BAY 80–6946. Median time on study was 129 days (3–487). Best response in 6 evaluable patients (FL, n=5, DLBCL, n=1) was 5 PR and 1 PD, all 5 evaluable FL patients achieving a PR, the longest of which is >16 months. Pharmacodynamic effects were demonstrated with significant lymphoma shrinkage observed as early as 48 hours after the first dose of BAY 80–6946 on 18FDG-PET/CT in both FL and DLBCL patients. Conclusions:In this MTD expansion cohort study in NHL lymphoma, BAY 80–6986 was generally well tolerated and showed very promising clinical activity in NHL patients. Updated clinical, PK and pharmacodynamic results will be presented. Based on these preliminary results, further clinical development as a single agent or in combination regimens in NHL is warranted. Disclosures:Patnaik:Bayer: Research Funding. Ramanathan:Bayer: Research Funding. Appleman:Bristol-Myers: Research Funding; Bayer Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Abbott: Research Funding; Cougar Biotechnology/Ortho Biotech: Research Funding; Medivation: Research Funding; Excelixis: Research Funding. Beerham:Bayer: Research Funding. Weiss:Bayer: Honoraria; Roche/Ventana: Honoraria; Merrimack: Honoraria; Cephalon: Honoraria; Eli Lilly: Honoraria; Cytrx: Consultancy; Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Caris Life Sciences: Speakers Bureau; Bayer: Research Funding. Rajagopalan:Bayer Pharmaceuticals: Employment. Jeffers:Bayer Pharmaceuticals: Employment. Kelly:Bayer Pharmaceuticals: Employment. Genvresse:Bayer Pharma AG: Employment.

Vorinostat (SAHA), Cladribine, and Rituximab in Previously Untreated Mantle Cell Lymphoma: Updated Results From a Phase I/II Trial

AbstractAbstract 3675 Background:Mantle cell lymphoma (MCL) remains incurable and little consensus exists on the best standard initial therapy. However, improved understanding of disease biology has the potential to lead to novel treatment approaches including new perspectives on older drugs. For example, epigenetic modifications including altered DNA methylation and histone acetylation previously identified in MCL has provided the rationale for using the combination of a hypomethylating agent and a histone deactylase inhibitor. Here we show that agents with differing mechanisms have significant activity in previously untreated MCL.In addition to its cytotoxic effects in lymphoid malignancies, cladribine has hypomethylating properties. Vorinostat (SAHA) is a histone deacetylase inhibitor (HDACi) FDA approved in cutaneous T cell lymphoma with modest single agent activity in MCL. Preclinically, the combination of these agents has been shown to activate silenced genes. Since cladribine inhibits DNA methylation via a unique mechanism, it could also potentially inhibit histone methylation.We previously reported initial results of our Phase I/II trial combining SAHA, cladribine, and rituximab (SCR) for the treatment of B-cell non-Hodgkin's Lymphoma (NHL) [Spurgeon et al, ASH, 2012]. Here we present the updated results from the Phase II portion of the trial in the untreated MCL cohort including response rate, overall and progression free survival, and correlative studies. Methods:The achieved phase II starting dose was vorinostat 400 mg po (days 1–14) combined with cladribine 5mg/m2 IV (days 1–5), and Rituximab 375 mg/m2 IV (weekly × 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Response evaluation occurs after 2 cycles and at the completion of therapy. Responding patients are eligible to receive maintenance rituximab. Phase II eligibility includes relapsed NHL as well as previously untreated MCL. The primary outcome is response rate (ORR); secondary endpoints include progression-free survival (PFS) and overall survival (OS). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray, qRT-PCR and HELP methylation analysis. To evaluate the possible effects of SAHA metabolism on toxicity and response, UDP-glucuronosyltransferase 2B17 (UGT2B17) genotyping is also performed. This study continues to enroll patients. Results:28 previously untreated MCL patients have been enrolled on the phase II portion of the study. 7 have not yet completed the planned 6 cycles; however, 26 patients have completed ≥ 2 cycles and are evaluable for response. The majority of responding patients have received maintenance rituximab. The overall response rate (ORR) is 100% (26/26) with 69% (18/26) achieving CR. Of those patients not attaining CR, 2 had blastic MCL and died, 3 have not yet completed active treatment, and 1 withdrew consent after two cycles. At a median follow up of 14.7 months (.07 – 25 months) 4 patients have relapsed and 3 have died. Of the relapsing patients, two had blastic MCL. None of the patients achieving a CR has relapsed. The estimated PFS curve (shown in the Kaplan-Meier curve below) did not reach the 0.5 level and therefore, median PFS could not be estimated. Toxicities were defined using CTCAE 4 and primarily include neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration. [Display omitted] We found that cladribine hypomethylates DNA in vivo (8/8 pts) and inhibits histone methylation in vitro. There were no upregulated genes common to untreated leukemic MCL patients; however, a number of changes in gene expression were observed. For example, upregulated genes after treatment included DUSP2 (3 patients), FOXO3 (2 patients), NOXA1 (2 patients), CEBPb (2 patients) and p53 (3 patients). Conclusions:The SCR regimen has significant activity and shows epigenetic activity in previously untreated MCL. Initial follow up results are promising, especially in patients without blastic MCL who continue with maintenance rituximab. The SCR regimen should be studied further in NHL. Disclosures:Spurgeon:Merck : Research Funding. Off Label Use: vorinostat: off label use mantle cell lymphoma. Epner:Merck: Research Funding, Speakers Bureau.

Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted.

AUTOLOGOUS STEM CELL TRANSPLANTATION FOR AGGRESSIVE LYMPHOMAS

The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL. In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.

The Plk1 inhibitor BI 2536 in patients with refractory or relapsed non-Hodgkin lymphoma: a phase I, open-label, single dose-escalation study

Polo-like kinase 1 (Plk1) is expressed during mitosis and overexpressed in multiple cancers, including non-Hodgkin lymphoma (NHL). This phase I study determined the maximum tolerated dose (MTD) of BI 2536, a Plk1 inhibitor, as a 1 h infusion once every 3 weeks in post-transplant relapsed (n = 17) and transplant-naive (n = 24) patients with relapsed/refractory NHL. Median treatment cycles were 2 and 1.5, respectively. MTD was 175 mg for both populations; dose-limiting toxicities were grade 4 thrombocytopenia and neutropenia. Most treatment-related adverse events were grade 1/2; drug-related grade 3/4 events included thrombocytopenia and neutropenia. Four patients achieved responses (three complete and one partial at doses ≥ 150 mg, all post-transplant relapsed patients) for an overall response rate of 9.8%. BI 2536 exhibited multi-compartmental pharmacokinetics with a high volume of distribution. The activity and safety of BI 2536 in this pretreated patient population support Plk inhibitors as a therapeutic strategy in oncology.

Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non-Hodgkin’s lymphoma

Allo-SCT is used to exploit GVL effect in high-risk relapsed non-Hodgkin's lymphoma (NHL). Here, we retrospectively analyzed 34 high-risk NHL patients who underwent auto-SCT followed closely by reduced-intensity allo-SCT ('tandem auto-allo') from January 2002 to November 2010. The search for an allogeneic donor was started at the beginning of salvage regimen. Median patients' age was 47 (27-68) years; histotypes were: diffuse large B-cell n=5, follicular n=14, transformed follicular n=4, mantle-cell n=5, plasmocytoid lymphoma n=1, anaplastic large T-cell n=2, peripheral T-cell n=3. Donors were HLA-identical siblings (n=29) or 10/10-matched unrelated individuals (n=5). Median interval between auto-SCT and allo-SCT was 77 days (36-197). At a median follow-up of 46 (8-108) months since allo-SCT, 5-year OS is 77% (61-93) and PFS is 68% (51-85). Disease relapse or progression occurred in six patients, 100-day TRM was 0%, 2-year TRM incidence was 6%. In conclusion, tandem transplantation is feasible in high-risk NHL patients having a HLA-identical donor. This approach could represent a suitable therapeutic option for those patients with high-risk NHL potentially benefitting from further therapy after auto-SCT. Donor searches should be started promptly whenever such an approach is chosen.

Pixantrone shows promise for relapsed non-Hodgkin lymphoma

Pixantrone shows promise for relapsed non-Hodgkin lymphoma

High-dose chemotherapy followed by allogeneic stem cell transplantation in high-risk relapsed and refractory aggressive non-Hodgkin lymphoma: Results of a prospective study of the German high-grade non-Hodgkin lymphoma study group.

8004 Background: The role of allogeneic stem cell transplantation (alloSCT) in high-risk aggressive NHL is poorly defined; the role of graft-versus-lymphoma effect is unclear. Reduced intensity conditioning has shown limited efficacy in patients with refractory disease. Methods: Patients with primary refractory disease, early relapse (&lt;12 months) or relapse after autologous SCT of aggressive B-cell (n=61) or T-cell (n=23) NHL were enrolled from June 2004 to March 2009. Myeloablative conditioning (fludarabine 125mg/m2, busulfan 12mg/kg, cyclophosphamide 120 mg/kg) was followed by alloSCT from related (n=24) or unrelated (n=60) donors. 57/84 patients received a 10 HLA-loci compatible graft. Results: Overall survival at 3 years was 42% (95% CI, 31% to 52%), progression-free survival (PFS) was 40% (95% CI 29% to 50%). Non-relapse mortality (NRM) was 12% at 100 days and 35% at one year. Graft-versus-host disease (GVHD) and infection were the predominant causes of NRM. Relapse rate was 30% with latest relapse at day +327. Patients with an HLA fully compatible donor (plus ATG with unrelated donors) (n=40) had the best outcome (NRM at 1y 10.4 vs 57.2%, PFS at 3y 64.7% vs 31.8%, p &lt; 0.0001). GVHD &gt; grade I correlated with improved PFS (HR 0.45, p=0.0088). Patients with refractory disease or early relapse (n=60) experienced PFS at 3y of 33%. Conclusions: Lymphoma-debulking (high-dose) chemotherapy followed by alloSCT shows excellent results in heavily pretreated patients with early relapse or primary refractory aggressive lymphoma. There was evidence of graft-versus-lymphoma activity in this setting. For patients with a fully matched (10/10) related or unrelated donor the results compare favorably to autoSCT or alloSCT following reduced-intensity conditioning.

Abstract 3776: Antitumor response to inotuzumab ozogamicin (INO) in patients with refractory or relapsed indolent B-cell non-Hodgkin's lymphomas (NHL): Pharmacokinetic-pharmacodynamic (PK-PD) modeling and interim results from a phase II study

Abstract Background: INO (CMC-544) is a novel antibody-drug conjugate composed of a CD22-directed IgG4 antibody linked to calicheamicin, a potent cytotoxin. In this phase II study, INO was administered 1.8 mg/m2 intravenously once every 28 days for a planned 4 to 8 cycles to patients with indolent B-cell NHL who were refractory to rituximab. Objective: The aim of this analysis was to evaluate the antitumor activity of INO by performing PK-PD modeling of the INO concentrations and tumor size (as determined from the sum of products of diameters). Methods: Analysis was performed with a set of 28 patients with indolent NHL (24 follicular, 2 small lymphocytic lymphoma, 2 marginal zone) having evaluable data at the interim stage of the study. Population PK-PD modeling was conducted using NONMEM v. 7.1.2. Longitudinal tumor size data included measurements from the pre-screen time, during INO therapy, and up to 15 months of follow up. The PK of total calicheamicin was described by a linear 2-compartment model. Tumor size (T) was described by an exponential net growth (kgr) model with an inhibitory drug effect (slope) on kgr and drug concentration (Cp), such that dT/dt = kgr(1-slope x Cp)T. Results: Of the 28 subjects evaluated, 18 exhibited tumor shrinkage (maximum reduction from baseline with a range of 12%-100% and a median of 68%), among which 10 were progression free/without tumor regrowth in the range of 10-18 months post first dose. Tumor shrinkage was seen as early as 54 days post treatment initiation, with peak tumor shrinkage as early as Day 103. The population estimates of clearance (CL), central (V1), peripheral (V2) volumes of distribution, and intercompartmental clearance (Q) were 2.69 (±0.41) L/day/m2, 30.4 (±1.79) L/m2, 90.9 (±19.8) L/m2 and 5.50 (±1.29) L/day/m2, respectively. The population parameter estimates of the PD model were 9.41 x 10−4 (±5.33 x 10−4) day−1 for kgr and 0.396 (±0.178) ng/mL−1 for the slope. Simulations from the model using 1,000 virtual subjects (1.8 mg/m2 every 28 days for a total of 4 cycles) showed that the median 10% tumor shrinkage can be seen as early as 35 days, with peak suppression occurring as early as 161 days. In addition, the duration of response was sustained beyond 1 year post treatment, and the tumor size does not return to baseline for up to 2 years after the first treatment. Conclusions: Antitumor response to INO in this study was characterized by a markedly long duration of response. PK-PD modeling improved the quantitative understanding of the time course of tumor size relative to inotuzumab treatment. The model, with updated data from the ongoing study, has utility in optimizing the dose and treatment regimen for subsequent follow-up studies in indolent lymphoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3776. doi:1538-7445.AM2012-3776