Initial Treatment of Diffuse Large B-Cell lymphoma (DLBCL)

R-CHOP 14 versus R-CHOP 21

Rituximab has become an integral part of the treatment of patients with B-cell NHL. However, the optimal way to incorporate rituximab into the overall treatment strategy for specific patients with NHL is still being intensely investigated. Researchers from Germany have previously reported that six cycles of R-CHOP14 is superior to six or eight cycles of CHOP14 or eight cycles of R-CHOP14 for treatment of diffuse large B-cell lymphoma (DLBCL). 

At ASCO 2009 researchers from the UK presented early data showing the safety of administering six cycles of R-CHOP 14 or eight cycles of R-CHOP 21 to patients with newly diagnosed DLBC NHL. This study enrolled 1080 patients with DLBCL with a median age of 61 years. This study is too early to evaluate efficacy but the safety of administration of six cycles of R-CHOP 14 was documented.

Autologous Stem Cell Transplantation

Previous studies have suggested that patients with diffuse DLBCL benefit from an autologous stem cell transplant after first relapse. The efficacy of transplantation as consolidation therapy in first remission, however, remains more controversial than salvage transplants.

At ASH 2008, researchers from France reported that high-dose chemotherapy and autologous stem cell transplantation as consolidation in first remission may benefit patients with DLBCL with poor-risk features. This study evaluated a regimen of rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in 209 patients with poor-risk DLBCL. Induction chemotherapy was delivered in four cycles at 15-day intervals. One hundred seventy-six patients (84%) responded, 61% had a complete response, and 155 (75%) received an autologous stem cell transplant following high-dose BEAM. The median follow-up was 37 months. The complete response (CR) rate following transplantation was 72%, the progression-free survival was 85%, and overall survival was 90%. Treatment-related deaths occurred in 4% of patients during induction, and there were four deaths during the transplant procedure (<2%). These authors suggest that the addition of rituximab to this regimen improved outcomes compared with previous studies and suggested that consolidation with stem cell transplantation also improved outcomes.

At ASCO 2009, these same researchers performed a case-control study comparing patients in the above study receiving R-ACVBP with similar patients receiving induction therapy with ACVBP without rituximab. They made the following observations:

• Three-year progression-free survival (PFS) was 75% for R-ACVBP versus 58% for ACVBP.
• Three-year overall survival (OS) was 78% for R-ACVBP versus 67% for ACVBP.
• In patients who received an autologous transplant the three-year OS was 89% for R-ACVBP versus 77% for ACVBP.

These authors concluded that “These results with R-ACVBP induction and consolidative auto-transplantation suggest a major survival benefit which needs confirmatory prospective study.”

Epratuzumab and Rituximab (ER-CHOP)

Epratuzumab is a humanized monoclonal antibody that targets CD22 antigen, found on the surface of B-lymphocytes. Epratuzumab is being evaluated in patients with Sjögren’s syndrome and severe systemic lupus erythematosus (SLE). The FDA granted a Fast Track designation for the evaluation of epratuzumab for the treatment of patients with SLE. Phase I-II clinical trials of epratuzumab have shown significant activity in patients with relapsed B-cell NHL. The combination of rituximab and epratuzumab is reported to be well tolerated and effective in patients with relapsed or refractory B-cell NHL. 

Researchers involved in a North Central Cancer Treatment Group N0489 Phase II trial have reported that combining epratuzumab and rituximab with CHOP 21 is feasible and promising for the treatment of newly diagnosed patients with DLBCL. They treated 78 patients with low-, intermediate- and high-risk DLBCL. The CR rate was 73% and did not differ between the three risk groups. Event-free survival (EFS) was 80% at 12 months. The 12-month PFS and OS were 82% and 88%, respectively, for the entire group. High-risk patients had a 12-month EFS of 77%, a 12-month PFS of 77%, and an OS of 85%. These authors suggest that a randomized trial is needed to determine the impact of adding epratuzumab to R-CHOP 21.

Rituximab for CD5+ DLBCL

Patients with CD5+ DLBCL, which is characterized clinically by a high frequency of central nervous system (CNS) relapse, comprise 5-10% of patients with DLBCL. Researchers from Japan evaluated the effects of rituximab in patients with CD5+ DLBCL in a retrospective study. This study involved 313 patients with CD5+ DLBCL who were treated with chemotherapy with or without rituximab. The CR rate was 81% for patients receiving rituximab and 65% for patients not receiving rituximab. The two-year OS was 68% for patients receiving rituximab and 54% for patients not receiving rituximab. The incidence of CNS relapse was 12% for the rituximab group and 11% for the no-rituximab group. These authors concluded that rituximab improved the outcomes of patients with CD5+ DLBCL but did not prevent CNS relapses.

Salvage Induction Therapy for Relapsed NHL

Autologous stem cell transplantation (ASCT) is the most effective treatment for patients with NHL who have failed primary therapy. However, many patients are not considered candidates due to age or significant co-morbid conditions. The usual regimens for such re-induction attempts prior to autologous stem cell transplant (ASCT) include DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, solumedrol, cytarabine, cisplatin), and R-ICE (rituximab, ifosfamide, carboplatin, etoposide). The addition of rituximab to these regimens appears to improve outcomes. Gemcitabine-based regimens have also been found to be effective for treatment of patients with NHL who have relapsed or are refractory. Oxaliplatin is also an active agent for the treatment of failed NHL and has less renal toxicity than is observed with cisplatin-based regimens. 

A randomized multi-center international study funded by the National Institutes of Health compared R-ICE versus R-DHAP followed by autologous stem cell transplantation in DLBCL. This study also had a second randomization to rituximab maintenance or placebo. The early conclusions of this study showed equivalent results of the two induction regimens but it was also observed that who had received prior rituximab did poorly. At ASCO 2009, researchers involved in the CORAL study presented data on the 396 patients included in this trial. The overall response rate (ORR) was 63.5% following R-ICE induction and 62.8% for R-DHAP. CRs were observed in 38% of patients. Autologous stem cell transplantation was performed in 206 patients. The three-year EFS was 26% for R-ICE and 35% for R-DHAP (p=0.6). The three-year OS was 47% for R-ICE and 51% for R-DHAP. Patients who had received prior rituximab had a three-year EFS of 21% versus 47% for rituximab naïve patients. This study is too early to evaluate the effects of rituximab maintenance.

Gemcitabine, Ifosfamide, Dexamethasone and Oxaliplatin

Researchers from Korea reported a 15% CR rate in 27 patients with refractory or relapsed aggressive NHL treated with three cycles gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX). Most of the patients in this study had DLBCL. The goal of the study was to prepare patients for an autologous stem cell transplant. The overall response rate was 52%. Toxicities were described as acceptable.

Rituximab, Oxaliplatin, Cytarabine, and Dexamethasone (ROAD)

Researchers from the Carle Clinic reported outcomes of 45 patients treated with a regimen of rituximab, oxaliplatin, cytarabine, and dexamethasone. Twenty of the patients in this study received all therapy in an outpatient setting. The ORR was 58% (n=26) and 20 responding patients proceeded to autologous transplantation. These authors suggest that the results of this trial were similar to those observed with R-DHAP but with less toxicity.

New Agents for the Treatment of Aggressive NHL

Pixantrone

Anthracyclines are among the most active anti-cancer compounds, especially for the treatment of NHL and breast cancer. The main long-term toxicity of anthracyclines is cardiac toxicity, which can become manifest many years after treatment has been discontinued. There have been attempts to decrease cardiotoxicity by pegylation and liposomal encapsulation. One mechanism thought to be responsible for the cardiac toxicity of anthracyclines is through the production of free radicals. Pixantrone was designed by eliminating OH molecules while retaining the rest of the mitoxantrone molecule. This agent was tested in a Phase I trial presented at ASH 2003. Researchers from France, Germany and Cell Therapeutics reported at ASH 2004 that pixantrone produced a high response rate without a decrease in cardiac function in patients with NHL previously treated with anthracyclines. 

AT ASCO 2009 researchers from the UK, India, and Peru presented data on 140 patients with aggressive NHL who had failed a median of three prior treatment regimens. Patients in this study were randomly allocated to receive salvage therapy with pixantrone or alternative single agent therapy (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, gemcitabine or rituximab). The CR rate was 20% in the pixantrone group and 6% in the control group. The ORR was 37% in the pixantrone group and 14% in the control group.

Flavopiridol

Flavopiridol is a cyclin-dependent kinase inhibitor that is being evaluated as a single agent and in combination with other agents for the treatment of CLL and NHL. Recent studies suggested that the efficacy of flavopiridol was schedule-dependent and associated with the release of IL-6, which led to hyperacute tumor lysis syndrome. This led to the development of a regimen that consisted of a 30-minute loading dose followed by a four-hour infusion that was administered weekly for four to six weeks. The results of this study were published in 2007 in Blood. The dose-limiting toxicity of this regimen was hyperacute tumor lysis syndrome due to cytokine release (IL-6), requiring aggressive prophylaxis and exclusion of patient with WBC counts >200X109/L. In this study 45% of 42 refractory patients achieved a partial response. These authors found significant activity of flavopiridol in patients with 17p13.1 cytogenetic abnormalities. These authors suggested that this agent is one of the most active agents in clinical trials for CLL.

At ASCO 2008, researchers from Ohio State University reported that flavopiridol has “pronounced” activity in treating patients with relapsed CLL. These same investigators reported at ASH 2008 that flavopiridol produces durable responses in patients with relapsed CLL with high-risk cytogenetic abnormalities. 

At ASCO 2009, researchers from the NCI and the Dana Farber Cancer Institute presented the results of a Phase I-II study of flavopiridol in 20 patients with relapsed/refractory mantle cell lymphoma or DLBCL. The PR rate was 10% and the stable disease (SD) rate was 25%. The Phase I part of this study has not been finished and the ultimate role of flavopiridol remains to be determined.

Iboctadekin (IL-18)

Iboctadekin is an immunostimulatory cytokine with potent antitumor activity in preclinical models. A Phase I study in patients with malignant melanoma was presented at ASCO 2006. Early results of a Phase I of iboctadekin and rituximab in patients with relapsed NHL was presented at ASCO 2009. Activity was observed but results are too early to determine if iboctadekin adds to the benefit of rituximab.

YM155, a Survivin Suppressant

Survivin is a member of the inhibitor of apoptosis (IAP) family which has become a target for cancer therapy. YM155, a small-molecule survivin suppressant, has demonstrated potent antiproliferative activity against a wide spectrum of human tumor cell lines. Phase I studies were performed in patients with solid tumors or lymphoma. At ASCO 2009, researchers involved in a multicenter US study reported that “YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients.” There were 35 patients in this study; one had a partial response and several others had stable disease.

Darinaparsin (ZIO-101)

Darinaparsin is an oral or intravenous small-molecule organic arsenical that is being evaluated in Phase I and II studies. At ASCO 2009, researchers involved in a multicenter US-Canadian trial concluded that “Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been well tolerated.” This study included 21 patients with NHL and seven with Hodgkin lymphoma treated with IV darinaparsin. Seven of 19 evaluable patients responded with minimal toxicity. There were three CRs and four PRs with four additional patients having SD. Responses were seen in peripheral T-cell lymphoma, DLBCL, and Hodgkin lymphoma.

Treatment of Primary CNS Lymphoma

Primary CNS lymphoma is a relatively uncommon form of lymphoma that has been increasing in incidence over the past three decades. Unlike the progress made in the general treatment of NHL, there has been little progress in the treatment of primary central nervous system NHL. The standard treatment is high-dose methotrexate and whole-brain radiotherapy which has improved outcomes. However, treatment-related neurotoxicity is common, especially in the elderly who often have poor renal function. One recent study has suggested that rituximab and temozolomide is an effective treatment regimen for patients with primary CNS NHL. Researchers from Germany have also reported that a high-dose regimen of carmustine and thiotepa appeared to improve outcomes of patients with primary CNS NHL when followed by whole brain radiation therapy. 

At ASCO 2009, researchers from Switzerland reported that the addition of high-dose cytarabine to high-dose methotrexate improved outcomes of patients with CNS NHL without prohibitive toxicity. This study included 79 patients between the ages of 18 and 75 years with newly diagnosed primary CNS NHL. Patients were randomly allocated to receive standard therapy with high-dose methotrexate or high-dose methotrexate with high-dose cytarabine. Complete responses were observed in 18% of patients receiving high-dose methotrexate alone and 46% for patients receiving high-dose cytarabine. The ORR’s were 40% and 69%, respectively. The three-year EFS rate was 21% for the high-dose methotrexate group and 38% for the high-dose cytarabine group. three-year OS rates were 32% and 46%, respectively.

Mantle Cell Lymphoma (MCL)

Lenalidomide

Lenalidomide is an orally administered derivative of thalidomide that has anti-angiogeneic properties as well as numerous immune and biologic properties. lenalidomide is approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma and myelodysplastic syndromes. Clinical trials have also documented activity in most subtypes of NHL. Researchers from the Mayo Clinic have also reported that lenalidomide has significant activity in patients with refractory MCL. This multicenter study included 15 patients with MCL who had failed prior therapy, including stem cell transplantation in five. The ORR was 53% with 20% (n=3) having a CR. The median duration of response was 14 months, and the median PFS was 5.6 months. Four of the five patients who had failed stem cell transplantation responded.

At ASCO 2009, researchers involved in an international multi-center trial reported outcomes of 54 patients with relapsed or refractory MCL treated with lenalidomide. The CR rate was 9%, the PR rate was 14%, and side effects were described as manageable.

Treatment of T-Cell Lymphomas

T-cell lymphomas are a relatively uncommon form of NHL that generally do not respond as well to treatment as B-cell NHL. Though patients with B-cell NHL benefited significantly from rituximab therapy over the past decade, there is no comparable T-cell antibody for treatment of T-cell lymphomas. High-dose chemotherapy with autologous stem cell transplants has been used with some success for the treatment of patients with T-cell lymphoma. However, even after ASCT the probability of recurrent disease is high. Allogeneic stem cell transplantation offers a more curative approach, but transplant-related mortality is high. The optimal approach to the treatment of T-cell lymphomas remains uncertain, and the prognosis for many patients is poor, especially those with peripheral T-cell lymphomas (PTCL).

Upfront Treatment of T-Cell Lymphoma

Bortezomib with ACVBP

Researchers from France presented the results of a GELA trial, LNH05-IT, which evaluated a regimen of bortezomib combined with ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone) for four courses followed by consolidation with bortezomib, methotrexate, etoposide, ifosfamide, cytarabine for four additional courses in 57 patients with PTCL. The CR rate was 45% after induction and 46% after consolidation. These authors suggest that bortezomib did not add to the response rate compared to ACVBP without bortezomib.

Treatment of Relapsed T-Cell Lymphoma

Pralatrexate

Pralatrexate inhibits dihydrofolate reductase (DHFR), a folic acid-dependent enzyme involved in the building of nucleic acids and other cellular processes. Pralatrexate is a small-molecular chemotherapy agent that is transported into tumor cells via the reduced folate carrier (RFC-1) and was designed for effective retention once inside tumor cells.

At ASH 2008 researchers involved in the PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial reported that 27% of patients with relapsed or refractory PTCL experienced a CR or PR following treatment with pralatrexate. 

At ASCO 2009 essentially the same data were presented. This study included 115 patients with PTCL, of whom, 109 were evaluable for efficacy. Sixteen percent of these patients had received a prior autologous stem cell transplant. The ORR was 27%. Ten percent of patients had a CR and 21% had SD. Patients appeared to respond after the first cycle of therapy. Responses appeared to be durable. In March of 2009, Allos Therapeutics, Inc. submitted a New Drug Application (NDA) to the US FDA for the use of pralatrexate for the treatment of patients with relapsed or refractory PTCL. The company has requested a priority review of this application.

Lenalidomide

At ASCO 2009 researchers from Canada presented data showing that lenalidomide has significant activity for the treatment of patients with T-cell lymphoma. They treated 24 patients with relapsed or refractory T-cell lymphoma. The ORR was 30% and two patients had SD. For responding and stable patients the median PFS was 169 days and the median OS had not been reached.

Vorinostat and bexarotene

Vorinostat is a histone deacetylase (HDAC) inhibitor, which was approved by the FDA in 2006 for treatment of CTCL. The HDAC inhibitors act by modulating both histone and non–histone targets. A number of non–histone proteins such as heat shock protein 90, HIF-1 alpha, and tubulin are acetylated by HDAC inhibitors. At ASCO 2008 researchers involved in the original study reported that six of 74 patients were still receiving vorinostat for two or more years. One of these patients had a CR, four a PR, and one with SD. These authors suggest that vorinostat can be administered safely for prolonged periods. A recent paper published in Blood described the results of treating 33 patients with refractory CTCL with vorinostat. Partial responses occurred in eight of 33 patients with 14 of 31 evaluable patients having relief of pruritis. The median time to treatment response was 12 months, the duration of response was 15 months and time to tumor progression was 30 months. 

Bexarotene is a retinoid that is approved by the FDA for the treatment of CTCL. Bexarotene selectively activates the RXR receptors that are responsible for biological properties such as apoptosis, inhibition of cell growth, differentiation and metastasis. A recent study from the UK showed a CR rate of 10%, a PR rate of 35%, and a SD rate of 23% in patients with mycosis fungoides or Sezary syndrome treated with bexarotene. 

At ASCO 2009 researchers from the UK performed a Phase I study of combining vorinostat with bexarotene in patients with CTCL. Responses were seen at higher dose levels but the doses of both drugs had to be reduced to avoid toxicity. The role of this drug combination will be determined in future Phase II trials.

Romidepsin

Romidepsin inhibits histone deacetylase (HDAC), resulting in alterations in gene expression and the induction of cell differentiation, cell cycle arrest, and apoptosis. This agent also inhibits hypoxia-induced angiogenesis and depletes several heat shock protein 90 (Hsp90)-dependent oncoproteins. Romidepsin has been given fast track status by the FDA for treatment of CTCL.

At ASH 2008 researchers involved in an international multicenter trial have reported that romidepsin is effective for the treatment of patients with CTCL. This study included 96 patients with CTCL who had failed at least one prior treatment. Seventy-two patients who received two or more cycles of therapy were evaluated for response. The ORR was 42% with 8% achieving a CR. Stable disease occurred in 26%, for an overall disease control rate of 78%. The median time to response was two months, and the median time to disease progression was nine months. Half the patients had relief of pruritis including severe pruritis. Toxicities were deemed tolerable and manageable.

AT ASCO 2009, data were presented on a total of 167 patients with CTCL who were treated with romidepsin following failure of other therapies. The ORR was 41%, the CR rate was 7%, and the median duration of response was 15 months. The median time to disease progression was eight months. The results of these two clinical trials demonstrate the effectiveness of romidepsin in CTCL.

Forodesine

Forodesine, a purine nucleoside phosphorylase inhibitor which has entered Phase I and II trials in patients with CTCL. AT ASCO 2009, researchers involved in a multicenter US study reported that “Forodesine has an acceptable safety profile and efficacy in CTCL subjects treated for 12 months or longer.” The ORR in the intent-to-treat population was 17 of 64 patients (27%) Nine of 64 patients (14%) received forodesine treatment for greater than 12 months. Of these nine patients, six discontinued treatment. Four patients discontinued treatment because of progressive disease, one withdrew consent and one discontinued due to an adverse event (diffuse large B-cell lymphoma). The median time on treatment for these six patients was 440 days. Through October 1, 2008, the other three patients remained on therapy for 416, 710 and 863 days, respectively. Of the nine patients that received forodesine treatment for 12 or more months, the most frequent adverse events were nausea, fatigue, peripheral edema, and dyspnea.

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