Beth Christian

A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma.

Ibrutinib has single agent activity of 22% to 68% in relapsed B-cell non-Hodgkin lymphoma(NHL). This study evaluated the safety and efficacy of ibrutinib combined with rituximab (R) and bendamustine. Patients received R (375 mg/m(2)) on day 1, bendamustine (90 mg/m(2)) on days 1 and 2, and ibrutinib (280 or 560 mg) on days 1 to 28 every 28 days for 6 cycles followed by ibrutinib alone until progression. Forty-eight patients enrolled, including 12 patients with follicular lymphoma (FL), 16 with diffuse large B-cell lymphoma (DLCL), and 17 with mantle cell lymphoma (MCL). No dose-limiting toxicities were observed. Patients received a median of 8 cycles, with 26 completing 6 cycles and continuing ibrutinib alone in cycles 7 to 34. The overall response (OR) rate was 72%, with 52% complete responses (CRs). By histology, the OR rate was 94% (76% CR) in MCL, 37% (31% CR) in DLCL, and 90% (50% CR) in FL. Grade 3 to 4 toxicities included lymphopenia (77%), neutropenia (33%), thrombocytopenia (19%), and rash (25%). Median progression-free survival has not been reached (95% CI, 8.7 months to not reached). The recommended phase 2 dose of ibrutinib in combination with R-bendamustine in patients with NHL is 560 mg. The combination has promising efficacy, particularly in MCL and FL. This trial was registered at www.clinicaltrials.gov as #NCT01479842.

Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

Flavopiridol in Chronic Lymphocytic Leukemia: A Concise Review

Patients with chronic lymphocytic leukemia (CLL) with high-risk cytogenetic features such as del(17p13) have limited treatment options and decreased overall survival. Dysfunction of p53 leads to resistance to fludarabine-based therapies. Cyclin-dependent kinase inhibitors (CDKi) are a novel class of agents that induce apoptosis in CLL cells independent of p53 mutational status. The synthetic flavone flavopiridol demonstrated promising in vitro activity in CLL. In initial phase I studies using a continuous infusion dosing schedule in a variety of malignancies, no clinical activity was observed. Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in vivo. In phase I testing, this dosing schedule resulted in acute tumor lysis syndrome (TLS) as the dose-limiting toxicity. With the implementation of a standardized protocol to prevent severe TLS, flavopiridol was administered safely, and responses were observed in heavily pretreated, fludarabine-refractory patients, cytogenetically high-risk patients, and patients with bulky lymphadenopathy. In a pharmacokinetic analysis, flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome. Phase II studies are under way with encouraging preliminary results. Flavopiridol is currently under active investigation in combination with other agents and as a means to eradicate minimal residual disease in patients following cytoreductive chemotherapy. Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review.

Flavopiridol in the treatment of chronic lymphocytic leukemia.

Purpose of review The synthetic flavone flavopiridol induces apoptosis of chronic lymphocytic leukemia cells in vitro; however, initial studies administering flavopiridol by a 24- to 72-h continuous intravenous infusion demonstrated no clinical activity. This review focuses on a novel dosing regimen that has achieved significant clinical activity in relapsed, poor-risk chronic lymphocytic leukemia. Recent findings Binding to human plasma proteins reduces free flavopiridol concentration and makes continuous intravenous infusion dosing ineffective. Pharmacokinetic modeling indicated that administering flavopiridol by a 30-min intravenous bolus followed by a 4-h continuous intravenous infusion would achieve serum concentrations necessary to induce in-vivo apoptosis. Our institution conducted a phase I study in relapsed chronic lymphocytic leukemia. Dose-limiting toxicity was acute tumor lysis syndrome resulting in fatal hyperkalemia. Careful monitoring and aggressive intervention for hyperkalemia, including hemodialysis if necessary, allowed flavopiridol to be given safely. Nineteen of 42 patients responded (45%), including five of 12 patients (42%) with del(17p13) and 13 of 18 patients (72%) with del(11q22). Summary Flavopiridol, when administered by a 30-min intravenous bolus followed by a 4-h continuous intravenous infusion, is active in high-risk, refractory chronic lymphocytic leukemia. Careful monitoring and aggressive intervention for tumor lysis syndrome and hyperkalemia is necessary for safe drug administration. Further studies to optimize the dose and schedule of administration, and to study this drug in other hematologic malignancies, are ongoing.

Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival.

Myc‐positive B‐cell non‐Hodgkin lymphoma (NHL) with or without a B‐cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) rearrangement is associated with inferior progression‐free survival (PFS) and overall survival (OS). In this study, the authors reviewed the outcomes of patients with myc‐positive and double‐hit NHL at The Ohio State University.

Antibody therapy for chronic lymphocytic leukemia.

The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemoimmunotherapy regimens in previously untreated patients. Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves complete response (CR) rates and prolongs progression-free survival (PFS), but a long-term survival benefit has not been shown. Alemtuzumab is less commonly used, due to the greater likelihood of infusion toxicity, as well as hematologic and immune toxicities. Subcutaneous (SC) administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus (CMV) reactivation, still occur with SC dosing. Alemtuzumabs unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate minimal residual disease (MRD) in bone marrow. Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study. Several investigational monoclonal antibodies are in preclinical or clinical studies, most notably lumiliximab (anti-CD23) and ofatumumab (HuMax CD20), and are briefly discussed in this review.

Mantle Cell Lymphoma 12 Years After Allogeneic Bone Marrow Transplantation Occurring Simultaneously in Recipient and Donor

A 34-year-old woman was diagnosed with chronic myeloid leukemia in chronic phase in October 1995 after she was found to have an elevated WBC count on routine evaluation. A six of six HLA-matched, sex-mismatched, ABO-mismatched, unrelated donor was identified from the National Marrow Donor Program pool, and in June 1996, the patient underwent a bone marrow transplantation. Her post-transplantation course was complicated by chronic graftversus-host disease. By December 2000, her immunosuppression for graft-versus-host disease was tapered off completely, and her chronic myeloid leukemia remained in morphologic, cytogenetic, and molecular remission. In April 2008, the patient developed cervical and inguinal lymphadenopathy. She underwent a biopsy of a right inguinal lymph node on May 20, 2008, which demonstrated mantle cell lymphoma (MCL) with immunohistochemistry confirming expression of nuclear cyclin D1. She had stage IVA disease with lymphadenopathy, a WBC of 5,200/ L, an absolute lymphocyte count of 900/ L, 5% peripheral blood involvement by flow cytometry, and bone marrow with 1.7% involvement by flow cytometry. Fluorescent in situ hybridization (FISH) analysis of the tumor cells in the lymph node specimen demonstrated that the malignant cells contained the Y chromosome, strongly suggesting that the MCL was donor derived. Figure 1A shows recipient MCL cells at the capsular region, with some of the lymphoma cells infiltrating into the capsules (hematoxylin and eosin H&E, 400). FISH (Fig 1B) highlights the lymphoma cells with XY chromosomes (one orange and one green) in the lymph node and infiltrating the capsule (white arrows), whereas host stroma cells have XX (double green) chromosomes (gold arrows, 1,000). FISH analysis of recipient peripheral blood mononuclear cells for the XY signal revealed 100% donor hematopoietic chimerism at the time of the patient’s MCL diagnosis. This prompted further evaluation of the origin of the MCL. The patient’s stem cell donor is a 61-year-old man who was diagnosed with MCL on May 5, 2008, during the same month as the recipient. He presented with dysphagia and weight loss and was found to have a 3.3-cm tonsillar mass. Biopsy of the mass demonstrated MCL cells (Fig 1C; hematoxylin and eosin, 200). Immunohistochemical staining for cyclin D1 (Fig 1D) demonstrated a homogenous nuclear stain ( 100). Staging studies demonstrated stage IVB disease

Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma.

Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin’s and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(−) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5–55 months), 7 patients relapsed (4 in the PET/CT(−) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30–0.85) vs 87% (95% CI: 0.57–0.97) in PET/CT(+) and PET/CT(−) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23–0.84) vs 100% in PET/CT(−) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.

Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkin's lymphoma

Flavopiridol is a broad cyclin‐dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a Phase I dose‐escalation study to determine the maximum tolerated dose (MTD) for single‐agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non‐Hodgkins lymphoma. Dose was escalated independently in one of four cohorts: indolent B‐cell (Cohort 1), mantle cell (Cohort 2), intermediate‐grade B‐cell including transformed lymphoma (Cohort 3), and T‐/NK‐cell excluding primary cutaneous disease (Cohort 4). Forty‐six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common nonhematologic toxicities included diarrhea and fatigue. Biochemical tumor lysis was observed in only two patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B‐cell). Dose‐limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6‐week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (two mantle cells, three indolent B‐cells, and one diffuse large B‐cell). The single‐agent activity of this first‐generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. Am. J. Hematol. 89:19–24, 2014.

The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma

As a result of the anti‐tumour activity observed in vitro and in vivo with combined anti‐CD20 and anti‐CD74 antibodies, we initiated a phase I/II trial of veltuzumab and milatuzumab in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma (NHL). Patients received an induction of veltuzumab 200 mg/m2 weekly combined with escalating doses of milatuzumab at 8, 16 and 20 mg/kg weekly for 4 weeks. Patients without disease progression could receive an extended induction with treatment on weeks 12, 20, 28 and 36. A total of 35 patients enrolled on the study. Median age was 63 years, median number of prior therapies was 3, and 63% of patients were rituximab refractory. No dose‐limiting toxicities were observed in the phase I study. Related grade 3–4 toxicities included lymphopenia, leucopenia, neutropenia, anaemia, infusion reactions, hyperglycaemia, fatigue and atrial tachycardia. Median weeks of therapy was 12 and 29% of patients completed all 36 weeks of therapy. The overall response rate was 24%, median duration of response was 12 months, and responses were observed at all dose levels and in 50% of patients refractory to rituximab. Combination therapy with veltuzumab and milatuzumab demonstrated activity in a population of heavily pre‐treated patients with relapsed or refractory indolent NHL.