The American Society of Clinical Oncology 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic Leukemia

The American Society of Clinical Oncology 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic Leukemia

At the 2008 meeting of the American Society of Clinical Oncology (ASCO), there were more than 100 abstracts devoted to the treatment of lymphoma. There is increasing evidence that survival of patients with lymphoma and chronic lymphocytic leukemia (CLL) is steadily increasing. New drugs are being developed at a reasonable rate, which creates the question of how best to incorporate all the available drugs in an optimal manner. Additionally, there appears to be significant progress in reduced-intensity allogeneic stem cell transplants for low-grade lymphomas.

Advances in Lymphoma

Epidemiology

Tricyclic Antidepressants: Researchers from Denmark reported that patients who are long-term takers of tricyclic antidepressant medications have an increased incidence of NHL.1 These data were also published in the July issue of Epidemiology.2 These researchers determined the incidence of NHL in 43,932 users of any antidepressant medication in North Jutland, Denmark, from 1989 through 2003. They reported that the use of tricyclic antidepressants was associated with an overall 53% increased incidence of NHL compared with nonuse. The risk was higher in users who had >10 prescriptions and more than five years of follow-up (IRR=2.50). The use of other types of antidepressants did not increase the risk of developing NHL.

Secondary Tumors in Lymphoma Patients

Risk of Lung Cancer in Patients with Lymphoma: Patients with one malignancy are at increased risk of developing a second malignancy. However, the magnitude of the risk varies from cancer to cancer and with different types of treatment. Very little has been written about the specific risk of lung cancers in patients with lymphoid malignancies. At ASCO 2008 researchers from Wayne State University used the SEER data base to evaluate the risk of developing lung cancer in patients with Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), or CLL.3

The current study found that 2% of 83,423 patients with HL, NHL, or CLL developed lung cancer. Patients with HL had a 300% increase in the incidence of lung cancer, 30% in NHL, and 60% in CLL. The increased incidence of other second primary cancers was 93% for HL, 8% for NHL, and 6% for CLL. The increased risk of developing lung cancer was greatest in the patients <50 years of age with relative risks of 4.57 for HD, 2.25 for NHL, and 3.42 for CLL. Patients >age 70 at diagnosis were not at increased risk of developing lung cancer. The median time to develop lung cancer was nine years for patients with HL, six years for patients with NHL, and five years for patients with CLL. The histology of lung cancers was non–small cell in 92% of cases and small cell in 8%. However, 15% of HL patients had small cell lung cancer.

The very high risk in HL may reflect the effects of radiation therapy, which is more frequent in HL than NHL (these data, however, were not presented). The major message of this presentation is that younger patients with lymphoma/CLL are at high risk of developing lung cancer and should be enrolled in screening programs.

Initial Treatment of Diffuse Large B-Cell NHL

Epratuzumab, Rituximab, and 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 been performed in patients with relapsed aggressive and low-grade B-cell NHL.4 5 The rationale for evaluating epratuzumab is that CD22 is widely expressed in B-cell malignancies. One trial evaluated epratuzumab in the treatment of patients with aggressive NHL that had recurred following previous therapies. This trial included 56 patients with relapsed/refractory NHL who had been treated on average with four prior therapeutic regimens. Twenty-five percent had failed treatment with high-dose therapy and stem cell transplantation. At the time of treatment with epratuzumab, 80% of patients had very advanced disease. Following treatment with epratuzumab, there were three complete and two partial responses, with six other patients having less than a partial response. The average duration of anticancer responses was 26 weeks, and the average duration of progression-free survival in patients who achieved a response was 35 weeks. Epratuzumab was very well tolerated. The researchers concluded that epratuzumab may provide an effective treatment option for patients with heavily pre-treated, aggressive NHL. This study also suggested activity against a variety of NHL histologies. At ASCO 2004 the preliminary results of a multicenter Phase II trial involving 65 patients with relapsed/refractory low-grade and high-grade NHL treated with rituximab and epratuzumab were presented.6 These authors reported a complete response rate of 23%. In another study the combination of rituximab and epratuzumab was reported to be well tolerated and effective in patients with relapsed or refractory B-cell NHL.7

At ASCO 2004 researchers from the Mayo Clinic and the University of Wisconsin presented preliminary data on combining epratuzumab and Rituxan with CHOP (ER-CHOP) for the treatment of newly diagnosed patients with diffuse large B-cell lymphoma.8 They reported that the response rate was reasonable with no added toxicities. At ASCO 2008 these same researchers presented data on 107 patients with newly diagnosed diffuse NHL treated with ER-CHOP.9 The complete response rate was 56%, the partial response rate was 38%, and two patients had stable disease. This relatively high response rate suggests that Phase III trials should be performed.

Treatment of NHL in the Elderly: The incidence of NHL increases with age, and an increase in the number of older patients with this disease is expected as patients live longer. However, very few, if any, very elderly patients are included in randomized trials evaluating different treatment regimens. Thus, the outcomes of treatment in various medical institutions become important. A previous study from Israel reported a high response rate in patients with NHL who are 80 years of age or older.10

Researchers from the University of Nebraska reported outcomes of 249 patients with NHL who were 80 years of age or older and were treated between 1982 and 2005.11 More than half the patients were treated with CHOP or similar combinations with or without rituximab. They reported an overall response rate of 86%. For all patients the probabilities of five-year progression-free survival and overall survival were 22% and 28%, respectively. A high age-adjusted international prognostic index was associated with a higher failure rate. Patients who completed four or more cycles of treatment or had radiation therapy had better outcomes. These authors concluded that anthracycline-based therapy was feasible in patients 80 years of age or older. However, the intensity of therapy was not tolerated in a many patients.

Researchers from the H. Lee Moffitt Cancer Center reported the outcomes of 107 patients with NHL over the age of 80 treated between 2000 and 2005.12 Twenty-eight percent received CHOP with or without rituximab, 42% received non-anthracycline containing regimens, and 30% were not treated. For the entire group, the one- and three-year survival rates were 61% and 22%, respectively. The median survival time was 21 months. Patients with indolent lymphoma had longer survivals than more aggressive lymphomas. Patients with aggressive NLH who received anthracyclines had better survivals than those receiving non-anthracycline regimens or no therapy. Chemotherapy did not appear to affect survival of patients with indolent NHL. These researchers concluded that CHOP and CHOP R improved survival of patients with aggressive NHL and that age alone should not be a contraindication to treatment.

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 ASCT include DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, solumedrol, cytarabine, cisplatin), and RICE (rituximab, ifosfamide, carboplatin, etoposide). The addition of rituximab to these regimens appears to improve outcomes.13 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.14

At ASCO 2008 researchers from M.D. Anderson Cancer Center presented data on 37 patients with relapsed aggressive NHL treated with gemcitabine, rituximab, oxaliplatin (GROC) and pegfilgrastim given every 14 days.15 The results were compared with other salvage regimens as shown in Table 1:

Table 1: Gemcitabine, Rituximab, Oxaliplatin (GROC) and Pegfilgrastim Given Every 14 Days in Patients with Relapsed Aggressive NHL

GROC

DHAP

ESHAP

RICE

No. Patients

37

63

85

34

Response Rate

81%

56%

58%

78%

CR Rate

41%

31%

38%

53%

Neutropenic Fever

5%

52%

30%

24%

Renal Toxicity

0

22%

22%

24%

Three-year Survival

33%

25%

32%

55%

The data on survival is apparently in patients not receiving ASCT. These authors also reported that 16 patients had a longer progression-free survival after GROC than after initial therapy. These authors concluded that GROC was as effective as the other commonly used salvage therapies with less toxicities.

Lenalidomide: An international study has found that lenalidomide has significant activity in patients with relapsed or refractory aggressive NHL.16 Lenalidomide, a derivative of thalidomide, is approved for treating multiple myeloma and myelodysplastic syndromes. In this study 79 patients with relapsed or refractory aggressive NHL were treated and 28% had an objective response. Favorable risk patients had a 50% response rate, and unfavorable risk patients had a 12% response rate.

In another analysis of the same study, 136 patients with relapsed or refractory NHL were treated with lenalidomide and evaluated for safety.17 The median dose of lenalidomide was 25 mg/day. The major side effects were neutropenia, rash, thrombocytopenia, constipation, anemia, diarrhea, pyrexia, nausea, and peripheral edema. Sixty-three patients remain on study at the time of this publication. These authors concluded that lenalidomide has a favorable safety profile.

Treatment of Peripheral T-Cell Lymphomas

T-cell lymphomas are a relatively uncommon form of NHL that generally do not respond as well to treatment than 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 ASCT 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. Recently, researchers from France affiliated with the Societe Francaise de Greffe de Moelle et de Therapies Cellulaire have reported that allogeneic SCT was effective therapy for patients with NK/T–cell lymphomas.18 This study reviewed the outcomes of 77 patients with aggressive T-cell or NK/T cell lymphoma who were treated with an allogeneic SCT. Fifty-seven patients received a myeloablative treatment regimen, and the remainder received a reduced-intensity treatment regimen. Sixty patients received transplants from related donors, and the remainder from unrelated donors. Fifty-seven of these patients were in complete or partial remission at the time of transplant. The five-year treatment-related mortality was 33%, overall survival was 57%, and event-free survival was 53%. Better outcomes were achieved in patients in complete or partial remission. Graft-versus host disease also increased mortality, especially in recipients of mismatched stem cells.

At ASCO 2008 researchers from Germany presented outcomes for 83 patients with peripheral T-cell NHL treated with ASCT who were in complete or partial remission.19 Prior to transplant patients in this study were treated with CHOP and Dexa BEAM. The transplant regimen was total body irradiation and cyclophosphamide. Fifty-five of the original 83 patients were ultimately transplanted; the main reason for not receiving a transplant was progressive disease. Following myeloablative treatment the complete remission rate was 56% and the partial remission rate was 8%. The three-year overall survival was 53%, and the three-year disease-free survival was 36%. These authors suggest that further improvements of pretransplant therapies are necessary.

Treatment of Cutaneous T-Cell Lymhoma (CTCL): Mycosis fungoides and Sezary syndrome are the most common forms of CTCL. Sezary syndrome has a leukemic form involving circulating Sezary cells. Mycosis fungoides can also evolve to a tumor stage with involvement of lymph nodes. Survival is determined by stage of the disease. Some patients with localized disease can survive for decades, while patients with systemic disease have an average survival of 3-4 years. Treatment consists of both topical and systemic therapies. Treatment modalities include psoralen and ultraviolet A radiation (PUVA), interferon alfa, local radiation therapy, electron beam therapy, bexarotene, topical chemotherapy, extracorporeal photochemotherapy, bexarotene, dinileukin diftitox, alemtuzumab, and the usual chemotherapy given for non-Hodgkin’s lymphoma. However, none of these therapies are curative. High-dose chemotherapy with autologous stem cell support is feasible in patients with CTCL, and though there is evidence of significant palliation, most, if not all, patients ultimately relapse. One potentially curative approach to refractory disease is an allogeneic stem cell transplant. However, allogeneic stem cell transplantation with intensive regimens is associated with high treatment related mortality and data on allogeneic stem cell transplants with reduced intensity regimens is limited due to the rarity of this disease.

Denileukin difitox (OTAK®) Denileukin diftitox is a fusion protein targeting the IL-2 receptor in malignant cells. Denileukin diftitox has been approved by the FDA since 1999 for the treatment of persistent and recurring CTCL. Denileukin diftitox has been evaluated in three large clinical trials administered in high and low doses for treatment of 307 patients with early or advanced CTCL.20 This evaluation also included 44 patients receiving a placebo. Table 2 summarizes the main findings of this trial:

Table 2: Denileukin Diftitox for Treatment of CTCL

Endpoint

Placebo

All Patients

CD25+

CD25-

Retreated

No. Patients

44

263

118

36

29

ORR

16%

38%

48%

31%

28%

CR

2.3%

9%

11%

8%

7%

PR

14%

29%

36%

22%

21%

PD

52%

18%

11%

25%

35%

Median PFS

124 days

794 days

870 days

>487 days

205 days

These authors concluded that denileukin diftitox had significant activity in patients with CTCL regardless of CD25 status. It was also of interest that there were spontaneous responses in patients receiving a placebo.

Vorinostat: 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.21 One of these patients had a complete response, four a partial response, and one with stable disease. These authors suggest that vorinostat can be administered safely for prolonged periods.

Treatment of Low-grade Lymphomas

Bendamustine and Rituximab in Older Patients: Bendamustine is a bifunctional agent with both alkylator and purine-like activity that is currently in Phase II testing in a variety of diseases. One advantage of bendamustine is that it is not cross-resistant with other alkylating agents. Bendamustine has been marketed and used clinically in Germany for many years in patients with NHL, CLL, multiple myeloma, breast cancer, and other solid tumors such as lung cancer. Betamustine is currently approved by the FDA for the treatment of CLL.

Researchers from Germany presented the results of treating 41 elderly patients with indolent or mantle cell lymphomas with bendamustine and rituximab.22 The median age of this group of patients was 79 years. The overall response rate was 88% with a CR rate of 35%. Major side effects were myelosuppression.

Treatment of Relapsed Low-grade Lymphomas

Autologous stem cell Transplants (SCT) for Relapsed Low-grade NHL: The efficacy of autologous SCT for patients with NHL may be compromised by residual disease remaining in the patient despite the high-dose therapy and the reintroduction of neoplastic cells with the autologous graft. Previous studies have suggested that the use of rituximab prior to stem cell collection can reduce the number of lymphoma cells in harvests. Rituximab can also be given after autologous SCT to decrease endogenous and exogenous sources of relapse.23 24

At ASCO 2008 researchers from Germany presented the results of autologous SCT in 34 patients with relapsed follicular or mantle cell lymphoma.25 All patients were in response after salvage therapy that included rituximab. The high dose chemotherapy was high-dose BEAM with rituximab in the 29 patients who were actually transplanted. Rituximab was administered as maintenance therapy. The five-year progression-free survival was 72% for patients with follicular lymphoma and 78% for mantle cell lymphoma.

Reduced-Intensity Allogeneic Stem Cell Transplants (SCT) for Relapsed Follicular Lymphoma: Patients with low-grade lymphoma, including CLL and follicular lymphoma, have many palliative treatment options, but ultimately virtually all patients become refractory to treatment. Some patients with low-grade lymphoma have a molecular marker, such as Bcl-2 or immunoglobulin (IG) gene rearrangement, which enables researchers to determine optimal response. The consensus of data suggests that survival is related to complete eradication of molecular evidence of disease. Allogeneic SCT is the most effective method of producing molecular remissions in patients with low-grade lymphomas. However, transplant-related mortality is high following conventional myeloablative regimens. Allogeneic stem cell transplants can be performed using reduced-intensity treatment regimens, which results in a lower treatment-related mortality rate and dependence on a graft-versus-tumor effect of the graft for the anti-lymphoma effect. However, there has been concern about the long-term effectiveness of this approach, with very little long-term data available. Researchers from Italy have previously reported that allogeneic SCT using a reduced intensity regimen of thiotepa, fludarabine, and cyclophosphamide results in high rate of complete clinical and molecular remissions in patients with relapsed or refractory chronic lymphocytic leukemia and follicular lymphoma.26 In this study the two-year disease-free survival was 100% for patients in molecular remission and 57% for those not in molecular remission.

Researchers from M.D. Anderson Cancer Center have recently reported that reduced-intensity allogeneic SCT resulted in an 83% progression-free survival with a 60 month follow-up in patients with relapsed follicular lymphoma (FL).27 The M.D. Anderson study reported outcomes of 47 patients with relapsed FL treated with a conditioning regimen of fludarabine, cyclophosphamide, and rituximab. All patients received an infusion of lymphocytes from related donors (n=45) or unrelated donors (n=2). All patients achieved a complete remission, and there have been only two relapses. Follow-up of this study is a median of 60 months, and the overall survival is 85%. All patients with molecular markers remain in complete remission (n=18). Severe acute graft-versus host disease (GVHD) occurred in 11%, and only five patients are receiving immunosuppression for chronic GVHD.

At ASCO 2008 researchers affiliated with the EBMT reported that reduced intensity allogeneic SCT from unrelated donors in patients with relapsed follicular lymphoma results in significantly prolonged survivals.28 This study included 93 patients who received a reduced intensity SCT and 51 patients who received a myeloablative SCT. All patients had failed multiple treatments, including autologous SCT in 47%. Table 3 summarizes the main findings of this study:

Table 3: Reduced Intensity SCT Versus Myeloablative SCT in Relapsed Follicular Lymphoma

Myeloablative SCT

Reduced Intensity SCT

Non-relapse mortality

46%

34%

Three-year PFS

35%

43%

Three-year OS

40%

49%

There were no differences in relapse rates between the two groups, and it was concluded that reduced-intensity unrelated donor SCT in follicular lymphoma may be superior to myeloablative SCT.

Autologous Versus Allogeneic SCT in Relapsed Follicular Lymphoma: Researchers affiliated with the Blood and Marrow Transplant Clinical Trials Network reported that allogeneic SCT may be superior to autologous SCT in patients with follicular lymphoma.29 This study evaluated the relative effectiveness of reduced-intensity allogeneic SCT in patients who had a matched sibling donor with autologous SCT in patients without a donor. Recipients of auto SCT receive an ablative regiment of total body irradiation, cyclophosphamide, and etoposide, while allogeneic recipients received a reduced-intensity regimen of fludarabine, cyclophosphamide, rituximab, tacrolimus, and methotrexate. All patients were in complete or partial remission prior to SCT. Table 4 summarizes the main findings of this study:

Table 4: Autologous Versus Allogeneic SCT in Relapsed Follicular Lymphoma

Number

OS

PFS

Relapse

NRM

Autologous

22

80%

69%

16%

15%

Allogeneic

8

100%

100%

0%

0%

Although the numbers of patients receiving allografts is small, the results are impressive and strongly suggest a graft-versus lymphoma effect in follicular lymphoma.

Treatment of Mucosa Associated Lymphoid Tissue (MALT) Lymphoma

Gastric MALT Lymphoma

Gastric MALT lymphoma is included, along with splenic marginal zone lymphoma, and nodal marginal zone lymphoma, in the group of lymphomas called marginal zone lymphomas. Gastric MALT lymphoma is the most common of the three and is associated with Helicobacter pylori (H. pylori) infection. Infections are also related to several other types of MALT syndromes. Although gastric MALT lymphoma is often caused by chronic H. pylori infection, MALT lymphoma of the skin can be associated with Borrelia burgdorfieri infection, MALT lymphoma around the eye can be associated with Chalamydia psittaci, and splenic marginal zone lymphoma is associated with Campylobacter jejuni.

Researchers from Taiwan have reported that treatment of H. pylori infection with antibiotics is effective against early-stage, low-grade gastric MALT lymphoma as well as high-grade transformed tumors.30 Researchers from Japan have also reported that H. pylori infection was present in 41 of 57 cases of gastric MALT lymphoma.31 They also reported that antibiotic therapy was effective therapy for the majority of H. pylori related MALT lymphomas and that radiation therapy was effective local therapy for H. pylori negative and antibiotic resistant lymphomas. Patients with gastric MALT who fail antibiotic therapy can be treated with radiotherapy or chemotherapy, though not all patients respond.

At ASCO 2008 researchers from Germany presented a 10-year follow-up of 120 patients with gastric MALT lymphoma treated with antibiotics.32 Eighty percent of patients in this study achieved a complete histological remission, and 80% of these patients remain in continuous complete remission. Seventeen percent showed histological residual disease after a median follow-up time of 32 months. With a watch-and-wait strategy, all but one of the patients with residual disease achieved a CR. In 24 patients secondary tumors occurred, which included eight lymphomas and 21 solid tumors. There were six gastric cancers in patients who were in CR from MALT. These researchers concluded that cure of H. pylori resulted in continuous CR in most patients. However, second cancers were a major concern. These authors recommended a watch-and-wait strategy with close follow-up.

Bortezomib for the Treatment of Refractory Gastric MALT Lymphomas:

At ASCO 2008 researchers from Italy presented the results of treatment of 16 patients with refractory gastric marginal zone MALT with bortezomib.33 After three cycles of therapy, eight patients had responded and four had a complete remission following treatment with bortezomib. Two patients with partial remissions converted to complete remissions with further therapy. Responses appeared to be durable.

Treatment of Extranodal Malt Lymphoma: At ASCO 2008 researchers presented the results of treating 22 newly diagnosed patients with extranodal MALT lymphoma with the combination of rituximab and fludarabine.34 Seventeen patients in this trial were evaluable for response, and 94% achieved a CR and the remainder a PR. Only one patient has relapsed at 15 months of follow-up.

Treatment of Relapsed CLL

Genasense® (Oblimersen, Bcl-2 Antisense): Researchers involved in a multicenter trial have reported that the addition of Genasenseto Fludara® (fludarabine) and Cytoxan® (cyclophosphamide) improves the survival of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who achieve a complete remission (CR) or near complete remission (nCR).35

Genasense is a Bcl-2 antisense oligodeoxynucleotide that is being evaluated for the treatment of multiple myeloma, acute myeloid leukemia, CLL, melanoma,and acute lymphoid leukemia. Bcl-2 is a potent inhibitor of apoptosis. Over-expression of this protein in patients with a variety of malignancies is associated with resistance to chemotherapy. Genasense down-regulates Bcl-2 and has been investigated in several hematologic malignancies where Bcl-2 has been implicated in disease resistance. In vitro studies suggest that Genasense can down-regulate Bcl-2 activity and inhibit cell viability.

Researchers from several institutions have previously reported the outcomes of 241 patients with advanced CLL treated with Fludara and Cytoxan with or without Genasense.36 The addition of Genasense increased the proportion of patients who achieve CR/nCR from 7% in the Fludara/Cytoxan only arm to 17% in the Genasense arm. Overall response rates were not different between the two groups. Maximum benefit was observed in Fludara-sensitive patients who had a four-fold increase in the CR/nCR rate. Responses were more durable in the patients receiving Genasense. The estimated median survival in the Genasense group was 33.8 months and 32.9 months in the chemotherapy-only group. The estimated three-year survival rate was 46% for the Genasense group and 37.5% for the chemotherapy-only group.

In the ASCO 2008 presentation, researchers reported a median duration of CR of 22 months in patients receiving Fludara and Cytoxan, while the median has not been reached for patients receiving Genasense. The median survival time for patients in CR has not been reached in the Genasense group compared with 46 months in the non-Genasense group. The researchers reported that 12 of the 20 patients achieving a CR were alive in the Genasense group versus three of eight patients receiving Fludara and Cyoxan without Genasense. CR was continuing in five of 12 in the Genasense group versus zero of three in the Fludara and Cytoxan group. It was concluded that the addition of Genasense to Fludara and Cytoxan increased the CR rate, CR duration, and survival of patients achieving CR. These authors also suggest that CR is a valuable endpoint in evaluating therapies for CLL.

Flavopiridol

Flavopiridol is a cyclin-dependent kinase inhibitior that is being evaluated as a single agent and in combination with other agents for the treatment of CLL. In one report published in 2005 flavopiridol was found to have “modest schedule-dependent clinical activity in relapsed CLL.37 However, another study, involving some of the same investigators concluded that flavopiridol had no activity in CLL.38 Stucies presented at ASCO 2006 suggested that pharmacokinetic modeling was necessary for optimal effects of flavopiridol in CLL.39,40 These studies led to regimen that consisted of a 30-minute loading dose followed by a four-hour infusion administered weekly for four to six weeks.41 The dose limiting toxicity of this regimen was hyperacute tumor lysis syndrome, which required aggressive prophylaxis and exclusion of patient with WBC counts >200,009/L. Forty-five percent of 42 refractory patients in this study achieved a partial response. These authors found significant activity of flavopiridol in patients with 17p13.1 cytogenetic abnormalities. They suggest that this agent is one of the most active agents in clinical trials for CLL.

At ASCO 2006 researchers presented data on the addition of flavopiridol to Fludara and Rituxan for the treatment of CLL and mantle cell lymphoma.42 In this clinical study, flavopironol was given by one-hour bolus infusion in addition to Fludara and Rituxan. These researchers reported significant clinical activity but significant toxicity. They are modifying the flavopiridol schedule and adding Neupogen® (filgrastim) to the regimen.

At ASCO 2008 researchers treated 62 patients with relapsed CLL with flavopiridol.43 Patients in this study were pretreated with dexamethasone to block the effects of IL-6 release during therapy. All were treated with a 30-minute bolus infusion followed by a four-hour infusion. Six and a half percent had a complete response and 42% a partial response. Responses were observed in 9/18 patients with adverse cytogenetics. These authors concluded that flavopiridol had “pronounced” activity in patients with relapsed CLL, including patients with bulky adenopathy and poor-risk cytogenetics.

Alemtuzumab

Alemtuzumab is the most effective agent in terms of efficacy for the treatment of patients with CLL who have failed both alkylating agents and fludarabine. Alemtuzumab is a fully human monoclonal antibody that selectively targets the CD52 antigen, which is expressed more prominently on malignant lymphocytes than other cells. The binding of alemtuzumab stimulates cellular lysis of the malignant lymphocytes and reduction or elimination of cancerous cells throughout the bone marrow, blood, and lymph system. In October of 2007, the U.S. Food and Drug Administration (FDA) approved alemtuzumab for initial treatment for patients with CLL. Side effects of alemtuzumab include an increased rate of infectious complications.

At ASCO researchers from Italy reported on a study evaluating whether a regimen of subcutaneously administered low-dose alemtuzumab would have decreased side effects.44 All patients in this study had 17p deletion and were unlikely to respond to alkylating agents. The median age for patients in this study was 74 years. The complete response rate was 7%, and the partial response rate was 33%. The median progression-free survival as 12 months for responding patients, and the median overall survival was 30 months. This regimen appeared to be well tolerated with no infectious deaths.

Alemtuzumab, Fludarabine, and Cyclophosphamide: German researchers reported the outcomes of 39 patients with relapsed or refractory CLL treated with the combination of alemtuzumab, fludarabine, and cyclophosphamide. The overall response rate was 70%, with 25% having a CR.45 This regimen was particularly effective in patients who had only received prior fludarabine and not fludarabine and cyclophosphamide.

Anti-CD23 Antibody (Lumiliximab): Lumiliximab is an anti-CD23 antibody being evaluated in patients with relapsed CLL. Researchers from the M.D. Anderson Cancer Center treated 31 patients with relapsed CLL with lumiliximab and fludarabine, cyclophosphamide, and rituximab (FCR).46 The complete response rate was 52%, and the partial response rate was 13%. The median progression-free survival was 19 months. Median progression-free survival for responders was 23 months.

Enbrel® (Etanercept): Etanercept is an anti-TNF agent used to treat rheumatoid arthritis. Researchers from Ohio State University presented data on combining rituximab with etanercept for the treatment of patients with relapsed CLL.47 The rationale for this study is the release of TNF by rituximab, which interferes with the killing of abnormal lymphocytes. This study included 36 patients with CLL or small cell lymphoma who had received a median of two prior regimens. The overall response rate was 29%, with similar response rates for fludaribine- sensitive and resistant patients. Responses were not affected by prior rituximab therapy, but there were no responses in patients with del (17p13.1). This regimen was thought to have promise in elderly patients not eligible for aggressive therapies.

Summary

The above abstracts suggest that more treatment options are now available for patients with lymphoma. There appears to be true progress in the treatment of some of the more rare forms of lymphoma such as MALT lymphoma, T-cell lymphoma, and possibly cutaneous T-cell lymphomas.

Reference:


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2 Dalton SO, Paulsen AH, Noergaard JK, et al. Tricyclic antidepressants and non-Hodgkin lymphoma. Epidemiology 2008;19:546-549.

3 Arunselvan SK, Schwartz A, Schiffer C, et al. Risk of lung cancer in Hodgkins (HL), non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL) patients (pts): Analysis of the Surveillance Epidemiology and End Results (SEER) data. Journal of Clinical Oncology 2008;26:abstract 8611.

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5 Leonard J, Coleman M, Ketas J, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2003; 21: 3051-3059.

6 Multi-centre, phase II study of combination antibody therapy with epratuzumab plus rituximab in relapsed/refractory indolent and aggressive NHL: Promising preliminary results. Journal of Clinical Oncology. 2004;23:577, abstract 6579.

7 Leonard JP, Coleman M, Ketas J, et al. Combination antibody therapy with epratuzumab and rituximab in relapsed/refractory non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2005;23:5044-5011.

8 Micallef IN, Kahl BS, Gayko U, et al. Initial results of a pilot study of epratuzumab and rituximab in combination with CHOP chemotherapy (ER-CHOP) in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). Journal of Clinical Oncology. 2004;23:577, abstract 6580.

9 Micallef IN, Maurer MJ, Nikcevich DA, et al. A phase II study of epratuzumab and rituximab in combination with cyclphosphamide, doxorubicin, vincristine and prednisone chemotherapy (ER-CHOP) in patients with previously untreated diffuse large B-cell lymphoma. Journal of Clinical Oncology. 2008;26:abstract number 8500.

10 Bairey O, Benjamini O, Blickstein D, et al. Non-Hodgkin’s lymphoma in patients 80 years of age or older. Annals of Oncology. 2006;17:928-934.

11 Koeneke TL, Wong P, RG Bociek, et al. Nebraska Lymphoma Study Group (NLSG) results for treatment for non-Hodgkin’s lymphoma (NHL). Journal of Clinical Oncology. 2008;26:abstract number 8534.

12 Nascimento FO, Soares HP, Ruiz A, et al. Treatment and survival of non-Hodgkin lymphoma patients over the age of 80. Journal of Clinical Oncology. 2008;26:abstract number 8569

13 Hicks L, Buckstein R, Mangel J, et al. Rituximab increases response to ESHAP in relapsed, refractory, and transformed aggressive B-cell lymphoma. Blood 2006;108:873a, abstract 3067.

14 Webb A, Cunningham D, Hill M, et al. An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin’s lymphoma. British Journal of Haematology. 2001;115:786-792.

15 Cabanillas F, Liboy I, Rodriguez-Monge E, et al. GROC (gemcitabine, rituximab, oxaliplatin combination) plus pegfilgrastim is less toxic and as active as DHAP and ESHAP for relapsed aggressive non-Hodgkin’s lymphoma (NHL). Journal of Clinical Oncology 2008;26:abstract 8530.

16 Czeuzman MS, Reeder CB, Polikoff J, et al. International study of lenalidomide in relapsed/refractory aggressive non-Hodgkin’s lymphoma. Journal of Clinical Oncology 2008;26:abstract 8509.

17 Habermann TM, Witzig TE, Lossos IS, et al. Safety of lenalidomide monotherapy in patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Journal of Clinical Oncology 2008;26:abstract 8603.

18 Le Gouill S, Milpied N, Buzyn A, et al. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: A study by the Societe Francaise de Greffe de Moelle et de Therapies Cellulaire. Journal of Clinical Oncology 2008;26:2264-2271.

19 Reimer P, Rudiger T, Einsele H, et al. Autologous stem cell transplantation (autoSCT) as first-line therapy in peripheral T cell lymphomas (PTCL): results of a prospective multicenter trial. Journal of Clinical Oncology 2008;26:abstract 8515.

20 Negro-Vilar A, Prince HM, Duvic M, et al. Efficacy and safety of enileukin diftitox (Dd) in cutaneous T-cell lymphoma (CTCL) patients: Integrated analysis of three large phase III trials. Journal of Clinical Oncology 2008;26:abstract 8551.

21 Olsen EA, Duvic M, Breneman D, et al. Vorinostat provides prolonged safety and clinical benefit to patients with advanced cutaneous t-cell lymphoma (CTCL). Journal of Clinical Oncology 2008;26:abstract 14588.

22 Rummel MJ, Heine K, Bodenstein M, et al. Efficacy and safety of bendamustine and rituximab in treatment of ndolent and mantle cell lymphomas in older patients. Journal of Clinical Oncology 2008;26:abstract 8572.

23 Belhadj K, Delfau-Larue M-H, Elgnaoui T, et al. Efficiency of In Vivo Purging with Rituximab Prior to Autologous Peripheral Blood Progenitor Cell Transplantation in B-Cell Non-Hodgin’s Lymphoma: A Single Institution Study. Annals of Oncology 2004;15:504-510.

24 Flinn IW, Diehl LF, Garrett E, Goodrich A, et al. Rituximab and Peripheral Blood Stem Cell Transplantation Produces Durable Remissions in Patients with Low Grade and Mantle Cell Lymphoma. Proc Am Soc Hem, Blood 2003;102(11):247a, Abstract #869.

25 Rupolo M, Michieli M, Manuele M, et al. Maintenance immunotherapy after autologous bone marrow transplantation (ABMT) in relapsed follicular (R-FL) and mantle cell (R-MC) lymphomas (NHL). A monoinstitutional experience. Journal of Clinical Oncology 2008;26:abstract 18012.

26 Farina L, Carrabba R, Milani R, et al. Molecular remission in relapsed/refractory chronic lymphocytic leukemia and follicular lymphoma treated with RIC-allogeneic stem cell transplantation correlates with a better disease-free survival. Bone Marrow Transplantation 2005;35 (supplement 2):S24, abstract number O138.

27 Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008;111:5530-5536.

28 Sureda A, Avivi I, Canals C, et al. Impact of the intensity of conditioning regimen in 144 patients with follicular lymphoma (FL) receiving a mathched unrelated stem cell transplant (MUD-SCT): an analysis form the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (LWP-EBMT). Journal of Clinical Oncology 2008;26:abstract 7036.

29 Laport G, Bredeson C, Tomblyn MR, et al. Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with follicular non-Hodgkins lymphoma (FL) beyond first complete response or first partial response. Journal of Clinical Oncology 2008;26:abstract 7041.

30 Chen L-T, Lin J-T, Tai JJ et al. Long-term results of anti-Helicobacter pyloritherapy in early-stage gastric high-grade transformed MALT lymphoma. Journal of the National Cancer Institute. 2005;97:1345-1353.

31 Akamatsu T, Mochizuki T, Okiyama Y, et al. Comparison of localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma with and without Helicobacter pylori infection. Helicobacter. 2006;11:86-95.

32 Wundisch T, Dieckhoff P, Gunther A, et al. 10-year follow up of 120 patients with gastric MALT lymphoma after Helicobacter pylori eradication-Histological residual disease and second cancers. Journal of Clinical Oncology 2008;26:abstract 8536.

33 Spadaro P, Pitini V, Toscano G, et al. Clinical activity of bortezomib in relapsed or refractory gastric marginal zone b-cell lymphoma of malt type. Journal of Clinical Oncology 2008;26:abstract 8567.

34 Salar A, Komingo-Domenech E, Estany C, et al. First-line treatment with rituximab combined with intravenous or oral fludarabine for patients with extranodal mucosa associated lymhoid tissue (MALT) lymphoma. Journal of Clinical Oncology 2008;26:abstract 8608.

35 Rai KR, Moore J, Wu J, et al. Effect of the addition of oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia (CLL) on survival in patients who achieve CR/nPT:Five –year follow-up from a randomized phase III study. Journal of Clinical Oncology 2008;26:abstract 7008.

36 O’Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. Journal of Clinical Oncology 2007;25:1114-1120.

37 Byrd JC, Peterson BL, Gabrilove J, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clinical Cancer Research. 2005;11:4176-4181.

38 Flinn IW, Byrd JC, Bartlett N, et al. Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leukemia Research. 2005;29:1253-1257.

39 Byrd JC, Lin TS, Dalton M, et al. Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 6516

40 Phalps MA, Wu D, Byrd JC, et al. Pharmacokinetic and pharmacodynamic correlations of lavopiridol in the treatment of chronic lymphocytic leukemia. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 12000.

41 Byrd JC, Lin TS, Dalton JT, et al. Flavorpiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007;109:399-404.

42 Flavopiridol, fludarabine and rituximab (FFR) is an active regimen in indolent B-cell proliferative disorders and mantle cell lymphoma (MCL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 7599.

43 Lin TS, Andritsos LA, Fisher JB, et al. Activity of the cylin-dependent kinase (CPK) inhibitor flavopiridol in relapsed, genetically high risk chronic leukemia (CLL). Journal of Clinical Oncology 2008;26:abstract 7007.

44 Pitini V, Arrigo C, Naro, et al. Subcutaneous low-dose alemtuzumab as first line therapy for elderly CLL patietns with delection of 17p. Journal of Clinical Oncology 2008;26:abstract 7048.

45 Elter T, James R, Wendtner CM, et al. Treatment of patients with relapsed/refractory CLL using a combination of fludarabine, cyclophosphaide and alemtuzumab: First safety analysis of the CLL2L trial of the German CLL Study Group. Journal of Clinical Oncology 2008;25: abstract 7053.

46 Byrd JC, Castro JE, Flinn IW, et al. Lumiliximab in combination with FCR for the treatment of relapsed chronic lymphocytic leukemia (CLL): results from a phase I/II multicenter study. Journal of Clinical Oncology 2008;25: abstract 7003.

47 Woyach JA, Lucas MS, Heerema NA, et al. Combination therapy with etanercept and rituximab in relapsed CLL/SLL. Journal of Clinical Oncology 2008;25: abstract 7065.

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