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Owen A O'Connor

Publications and source records attributed to Owen A O'Connor.

At least 19 recordsLinked to original sources
PubMed2006

Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma.

PURPOSE: Evaluate response rate, duration of response (DOR), time-to-progression (TTP), overall survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma (MCL). PATIENTS AND METHODS: Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 17 cycles. Response and progression were determined using International Workshop Response Criteria, both using data from independent radiology review and by the investigators. Primary efficacy analyses were based on data from independent radiology review. RESULTS: In total, 155 patients were treated. Median number of prior therapies was one (range, one to three). Response rate in 141 assessable patients was 33% including 8% complete response (CR)/unconfirmed CR. Median DOR was 9.2 months. Median TTP was 6.2 months. Results by investigator assessments were similar. Median OS has not been reached after a median follow-up of 13.4 months. The safety profile of bortezomib was similar to previous experience in relapsed multiple myeloma. The most common adverse events grade 3 or higher were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Death from causes that were considered to be treatment related was reported for 3% of patients. CONCLUSION: These results confirm the activity of bortezomib in relapsed or refractory MCL, with predictable and manageable toxicities. Bortezomib provides significant clinical activity in terms of durable and complete responses, and may therefore represent a new treatment option for this population with usually very poor outcome. Studies of bortezomib-based combinations in MCL are ongoing.

Adult↗
PubMed2006

The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide.

PURPOSE: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. EXPERIMENTAL DESIGN: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. RESULTS: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. CONCLUSION: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.

Animals↗
PubMed2006

The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma.

PURPOSE: Methotrexate is known to synergize with cytarabine [1-beta-D-arabinofuranosylcytosine (ara-C)] in a schedule-dependent manner. The purpose of this article is to compare and contrast the activity of pralatrexate (10-propargyl-10-deazaminopterin)/gemcitabine to the standard combination of methotrexate/ara-C and to determine if schedule dependency of this combination is important in lymphoma. EXPERIMENT DESIGN: Cytotoxicity assays using the standard trypan blue exclusion assay were used to explore the in vitro activity of pralatrexate and gemcitabine against a panel of lymphoma cell lines. Both severe combined imunodeficient beige and irradiated nonobese diabetic/severe combined imunodeficient mouse xenograft models were used to compare and contrast the in vivo activity of these combinations as a function of schedule. In addition, apoptosis assays were conducted. RESULTS: Compared with methotrexate-containing combinations, pralatrexate plus gemcitabine combinations displayed improved therapeutic activity with some schedule dependency. The combination of pralatrexate and gemcitabine was superior to any methotrexate and ara-C combination in inducing apoptosis and in activating caspase-3. In vivo, the best therapeutic effects were obtained with the sequence of pralatrexate --> gemcitabine. Complete remissions were only appreciated in animals receiving pralatrexate followed by gemcitabine. CONCLUSIONS: These data show that the combination of pralatrexate followed by gemcitabine was superior to methotrexate/ara-C in vitro and in vivo, and was far more potent in inducing apoptosis in a large B-cell lymphoma. These data provide strong rationale for further study of this combination in lymphomas where methotrexate and ara-C are used.

Aminopterin↗
PubMed2006

New drugs for the treatment of advanced-stage diffuse large cell lymphomas.

The rapid pace of discovering new signaling pathways that influence the growth and survival of different types of cancer cells has produced a daunting array of potentially new, "drugable" targets for the treatment of cancer. This has been particularly true for the lymphomas. The empiric observation that many kinds of "novel targeted" drugs appear to exhibit relatively selective patterns of activity is testament to the concept that the lymphomas represent an incredibly diverse group of human cancers. Targeting one pathway in a subtype of lymphoma may not be universally effective against all subtypes of lymphoma, even closely related ones. These observations suggest that pharmacologically driven "target identification" plays an important role in the continued development of new therapeutic agents, and underscores the need for more research into the biologic basis for different subtypes of lymphoma. Over the past 10 years, there has been an explosion of new drugs making their way through preclinical laboratories and early clinical studies. These experiences have taught us some frustrating lessons. Sometimes, the strongest biologic rationale is associated with the poorest clinical results. Sometimes, where no rationale exists, golden therapeutic opportunities emerge. In either case, both experiences typically end up teaching us something about the disease we didn't historically appreciate. In this review, we will take a close look at some of the more intriguing targets in aggressive large B-cell lymphomas, all of which now have small molecules that can profoundly affect their activity, activity we hope will lead to new treatment opportunities. We will focus on the biologic rationale for targeting novel pathways regulated by Bcl-6, Bcl-2, BLysS, and APRIL for example. In addition, we will review how new concepts in structural biology and chemical design can help produce new generation compounds with novel activity, as is the case for pralatrexate and targeting the reduced folate carrier-type-1. Clearly, given the breadth and depth of information emerging on these and other relevant biologic pathways, we are limited to discussing only a few illustrative examples, which should in no way detract from the importance of other critical signaling and survival pathways now being exploited in the treatment of lymphoma.

Antibodies, Monoclonal↗
PubMed2006

Pegylated interferon plus rituximab in advanced stage, indolent lymphoma: is there CD20 antigen upregulation?

The anti-CD20 monoclonal antibody, rituximab, and interferon alpha (IFN) are active agents in advanced stage, indolent lymphoma. Some data obtained in vitro suggest upregulation of CD20 by IFN, and clinical trials have reported additive or synergistic activity of IFN with rituximab. A prospective phase II study in advanced stage, follicular and non-follicular indolent lymphoma was performed. Peginterferon alpha 2b (pegIFN) 0.5 microg/kg s.c. weekly x 6 and rituximab 375 mg/m2 i.v. weekly x 4 (beginning on week 3 of pegIFN) was administered. Quantitative CD20 antigen was measured pre-treatment and pre-rituximab in lymph node aspirates. Nine patients were treated: one complete response and three partial responses; however, all relapsed within 12 months and two were withdrawn for grade 3 toxicity (both with serum sickness). No up-regulation of CD20 was documented in seven patients studied (median change in CD20: decrease by 11.9%). PegIFN plus rituximab as delivered in this study is not recommended. PegIFN does not appear to upregulate CD20 expression in peripheral lymph node tumor cells.

Aged↗
PubMed2006

Pralatrexate: an emerging new agent with activity in T-cell lymphomas.

PURPOSE OF REVIEW: T-cell lymphomas (TCL) represent a particularly poor prognosis subgroup of lymphomas. The goal of this review is to provide emerging information on one agent demonstrating activity in these challenging diseases. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1 (RFC-1). Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against TCL. RECENT FINDINGS: The high affinity of pralatrexate for RFC-1 significantly improves its internalization into cells. Preclinical studies in models of B-cell lymphomas and TCL have demonstrated that pralatrexate demonstrates activity superior to traditional antifolates. Phase I studies have shown the dose-limiting toxicity to be stomatitis, which can be abrogated with folic acid and vitamin B12 supplementation. Early phase studies have shown marked activity across a diverse panoply of TCL. SUMMARY: Pralatrexate is an antifolate designed to be internalized more rapidly than other traditional antifolates. Preclinical studies have demonstrated its superiority to methotrexate, and early phase I and II studies have shown marked activity across many poor-risk subtypes of TCL. Future studies are directed towards understanding the pharmacokinetic features of the drug, and expanding the population of patients with TCL and B-cell lymphomas.

Aminopterin↗
PubMed2006

Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response?

Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non-Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy. Punch biopsy in six patients revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, consistent with a non-necrotising cutaneous vasculitis. The combined overall response rate was 41%. The response in the 26 patients who developed a rash was 73%, compared with 33% in patients who did not. The odds ratio for response given the development of a rash was 4.6 (95% CI, 1.7-12.4, P = 0.001). This is the first report to characterise a vasculitic rash associated with bortezomib, and to show a relationship between development of the rash and response to treatment. Unlike classic hypersensitivity type reactions, this vasculitic rash may not necessarily prompt cessation of drug. In fact, the development of an isolated cutaneous vasculitis may portend a better clinical response to bortezomib in some patients.

Aged↗
PubMed2006

Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas.

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.

Boronic Acids↗
PubMed2005

Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies.

PURPOSE: To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies. PATIENTS AND METHODS: Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count > or = 500/microL and a platelet count more than 25,000/mL. All patients provided informed consent for study inclusion. RESULTS: A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lymphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis. Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR). One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months. CONCLUSION: These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma.

Administration, Oral↗
PubMed2005

Targeting histones and proteasomes: new strategies for the treatment of lymphoma.

Our ever-increasing understanding of cancer cell biology has begun to provide a variety of new, and potentially drugable targets for the treatment of many forms of cancer. Nowhere else is this more apparent than in the treatment of the lymphomas. A rapidly emerging experience in gene expression profiling has begun to suggest that we can define different subtypes of lymphoma on the basis of unique molecular signatures. These signatures can define important signaling pathways that may help account for the biology of different subsets of lymphoma, and are teaching us that the lymphomas are truly a heterogeneous set of diseases. What remains equally as interesting is the idea that empiric observations of novel targeted drugs in select subtypes of lymphoma can teach us much about the biology of different lymphomas. A priori assumptions about the anticipated activity of novel targeted agents in select subtypes of lymphoma have been turned upside down. Two pathways that have emerged recently as potentially important targets for new agents in lymphoma include the ubiquitin proteasome pathway and the biochemical reactions that control histone acetylation. New classes of drugs that affect these targets, such as bortezomib, depsipeptide, suberoylanilide hydroxamic acid, and a host of other compounds, though affecting a unique target in the cell, are associated with a remarkable panoply of different downstream biologic effects. In this article, we will review some of the prevailing theories about how these novel targeted drugs affect lymphoma biology, and how these compounds are changing the face of lymphoma therapy.

Antineoplastic Agents↗
PubMed2005

Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer.

PURPOSE: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. PATIENTS AND METHODS: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. RESULTS: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. CONCLUSIONS: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

Administration, Oral↗
PubMed2005

R-CHOP-14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy.

Treatment of diffuse large B-cell lymphoma (DLBCL) with CHOP-21 (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg for 5 days every 21 days) results in long-term remission in approximately 45% of patients. Recent phase III trials have demonstrated improved survival by modifying CHOP either through adding rituximab or shortening the time between cycles to 14 days. These studies prompted our institution to treat newly diagnosed patients with DLBCL refusing or not eligible for protocol-based therapy with R-CHOP-14. In this single-institution retrospective analysis, we report our results with this regimen. Forty-nine patients with newly diagnosed DLBCL and ineligible or refusing protocol-based therapy were retrospectively identified. Patients were treated with 6-8 cycles of R-CHOP-14 given with filgrastim and prophylactic antibiotics. The main toxicities with R-CHOP-14 were hematological and neurological and were not unexpected. There were no treatment-related deaths. Patients received 90% of planned cytotoxic drug density. The complete remission/complete remission uncertain (CR/CRu) rate was 82.2%. At a median follow-up of 24 months, the event-free survival was 80% and overall survival 90%. These results demonstrate R-CHOP-14 can be given to patients safely and short-term results regarding survival are promising. Whether adding rituximab and increasing dose intensity improves survival over either alone will require randomized studies.

Antibodies, Monoclonal↗
PubMed2005

Comparative animal models for the study of lymphohematopoietic tumors: strengths and limitations of present approaches.

The lymphomas probably represent the most complex and heterogenous set of malignancies known to cancer medicine. Underneath the single term lymphoma exist some of the fastest growing cancers known to science (i.e Burkitt's and lymphoblastic lymphoma), as well as some of the slowest growing (i.e. small lymphocytic lymphoma [SLL] and follicular lymphoma). It is this very biology that can dictate the selection of drugs and treatment approaches for managing these patients, strategies that can range from very aggressive combination chemotherapy administered in an intensive care unit (for example, patients with Burkitt's lymphoma), to watch and wait approaches that may go on for years in patients with SLL. This impressive spectrum of biology emerges from a relatively restricted number of molecular defects. The importance of these different molecular defects is of course greatly influenced by the intrinsic biology that defines the lymphocyte at its different stages of differentiation and maturation. It is precisely this molecular understanding that is beginning to form the basis for a new approach to thinking about lymphoma, and novel approaches to its management. Unfortunately, while our understanding of human lymphoma has blossomed, our ability to generate appropriate animal models reflective of this biology has not. Most preclinical models of these diseases still rely upon sub-cutaneous xenograft models of only the most aggressive lymphomas like Burkitt's lymphoma. While these models clearly serve an important role in understanding biology, and perhaps more importantly, in identifying promising new drugs for these diseases, they fall short in truly representing the broader, more heterogenous biology found in patients. Clearly, depending upon the questions being posed, or the types of drugs being studied, the best model to employ may vary from situation to situation. In this article, we will review the numerous complexities associated with various animal models of lymphoma, and will try to explore several alternative models which might serve as better in vivo.

Animals↗
PubMed2005

Developing new drugs for the treatment of lymphoma.

Despite the great progress that has been made over the last several decades in the treatment of lymphoma, the prognosis for patients with relapsed disease, and particular sub-types of lymphoma like mantle cell and T cell lymphoma, remains quite poor. While major advances in the use of combination chemotherapy, monoclonal antibodies, peripheral blood stem cell transplants, and radioimmunotherapy, have provided new opportunities to alter the natural history of these diseases, and even improve cure rates among elected sub-populations of patients, these 'traditional' approaches have not benefited all patients, or subtypes of lymphoma. The incredibly rapid pace of understanding the molecular basis for the discrete sub-types of both non-Hodgkin's lymphoma and Hodgkin's Disease is beginning to afford exciting new opportunities to both risk stratify patients, and to identify potentially novel 'drugable' targets. These advancements in understanding the major molecular defects in lymphoma, have provided a new context in which we can rethink the use of new and old drugs, and design new ones with unique mechanisms of action. The panoply of new targets and drugs now becoming available for the treatment of lymphoma is truly daunting. A plethora of new small molecules that target bcl-2, mTOR, histone deactylases, and NF-kB have shown promising preclinical activity, and are now promising early phase activity. In many cases, the empirical observations from early clinical trials have provided invaluable clues to potentially valuable drugs like bortezomib, depsipeptide, and SAHA, These empirical observations, based on the inclusion of patients with lymphoma on these studies, have thus far proven to be as or more valuable than any other 'rational' target based approach. In addition, beyond the novel small molecules affecting unique and heretofore unrecognized biological pathways, there continues to be a robust and important effort to identify new derivatives of older generation drugs with hopefully better activity, and less toxicity. For example, new generation anthracenediones and anti-folates, and new formations of older drugs like doxorubicin, irinotecan, and vincristine afford new opportunities to favourably change the pharmacokinetic profile of these agents, and improve their overall safety profile. While it would not be possible to address each and every new such drug, we hope to touch on some of the major new themes and agents emerging for the treatment of Hodgkin's Disease and non-Hodgkin's lymphoma.

Antineoplastic Agents↗
PubMed2005

Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma.

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.

Boronic Acids↗
PubMed2004

Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.

PURPOSE: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/microL (500/microL if documented bone marrow involvement); and platelet count more than 50,000/microL. RESULTS: Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). CONCLUSION: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.

Adult↗
PubMed2004

The emerging role of bortezomib in the treatment of indolent non-Hodgkin's and mantle cell lymphomas.

The elucidation of detailed new signaling pathways in normal cells and how their perturbation contributes to the development of the malignant phenotype has created innumerable venues for the development of novel drugs that can affect these targets in therapeutically meaningful ways. For example, our understanding of the complex biology underlying the ubiquitin-proteasome pathway in normal cells has recently led to the identification of specific agents capable of affecting this biology. Intuitively, one would not presume that inhibiting such a ubiquitous and essential biologic process, such as the ubiquitin-proteasome pathway, would lead to a new therapeutic strategy in cancer patients, although empirical evidence has suggested otherwise. The proteasome is a complex structure of many proteins, some of which are specific proteases, that play a critical role in regulating the balance of intracellular protein. Bortezomib, formerly known as PS-341, is a very potent and selective inhibitor of the chymotryptic-like enzymatic function residing in the 26S proteasome. Inhibition of this particular enzymatic activity has now been associated with an enormous panoply of different biologic effects, including everything from the regulation of nuclear factor-kappaB to the stabilization of cell-cycle regulatory proteins and the induction of apoptosis through the upregulation of specific proapoptotic proteins. Inhibiting this particular enzymatic function has now been associated with sometimes dramatic clinical effects in a variety of hematologic malignancies, including multiple myeloma and non-Hodgkin's lymphoma. This activity has led to the recent US Food and Drug Administration approval of bortezomib for the treatment of relapsed or refractory multiple myeloma. This activity has also spawned several clinical studies that have now clearly established activity in a host of different lymphoma subtypes, including the challenging mantle cell lymphomas. These data are simply the tip of the iceberg and will no doubt continue to provide fodder for many years of innovative scientific and clinical development. This development will likely lead to the eventual integration of this promising new class of molecules into the mainstream treatment of many hematologic malignancies, including myeloma and hopefully several different non-Hodgkin's lymphomas. Understanding how precisely to integrate these novel compounds will require us to learn more regarding the array of different biologic effects proteasome inhibitors have on the cell and how these effects can be further augmented with conventional chemotherapy drugs. The story is testament to the value of recognizing the importance of empiric observations in clinical and preclinical investigations.

Antineoplastic Agents↗