Also known as: Treanda
Canadian Status: Bendamustine is not yet approved in Canada for the treatment of follicular lymphoma. However, it is currently being used in several Canadian clinical trials, including a comparison of rituximab + bendamustine with R-CHOP/R-CVP.
Showing posts with label Drug Therapy. Show all posts
Showing posts with label Drug Therapy. Show all posts
Wednesday, January 12, 2011
Tuesday, January 4, 2011
Watch & Wait in Follicular Lymphoma
Follicular lymphoma is indolent (slow-growing), and (at least for the moment) incurable. For this reason, studies have shown in the past that there is no benefit to beginning immediate treatment per se. The exception is in early, localized disease, when chemotherapy and radiation treatment may be able to effect a cure. Most patients have advanced (Stage III or Stage IV) disease at diagnosis, but have no symptoms (are "asymptomatic") other than swollen lymph nodes.
That doesn't mean "watch & wait" is a comforting strategy for patients, though. Quite the contrary -- "watch & worry," as the less formal title for this strategy goes, can be a time of great stress and anxiety. For this reason, it's important to know the arguments for and against watch and wait, to determine whether this really is beneficial for you and your loved one.
How Watch & Wait (W&W) Works
Nervous patients understandably put the emphasis on the "wait" part. Oncologists tend to put the emphasis on the "watch" part. During watch and wait, patients check in with their physician on an established schedule, such as every three tests. Palpable (feelable) lymph nodes are examined, blood counts are taken, and standard scans (such as CT scans) are ordered, and the results are compared with those of the previous examination. For most patients, follicular lymphoma grows slowly, and these checkups allow the doctor and patient to monitor the progress of the disease. Eventually, usually when symptoms appear (criteria are discussed in further detail below), watch and wait ends and treatment begins.
That doesn't mean "watch & wait" is a comforting strategy for patients, though. Quite the contrary -- "watch & worry," as the less formal title for this strategy goes, can be a time of great stress and anxiety. For this reason, it's important to know the arguments for and against watch and wait, to determine whether this really is beneficial for you and your loved one.
How Watch & Wait (W&W) Works
Nervous patients understandably put the emphasis on the "wait" part. Oncologists tend to put the emphasis on the "watch" part. During watch and wait, patients check in with their physician on an established schedule, such as every three tests. Palpable (feelable) lymph nodes are examined, blood counts are taken, and standard scans (such as CT scans) are ordered, and the results are compared with those of the previous examination. For most patients, follicular lymphoma grows slowly, and these checkups allow the doctor and patient to monitor the progress of the disease. Eventually, usually when symptoms appear (criteria are discussed in further detail below), watch and wait ends and treatment begins.
Tuesday, December 21, 2010
Rituximab Maintenance: New PRIMA Trial Data
The Lancet's Online First section has released a new set of data from the major Primary Rituximab and Maintenance Study (PRIMA), a massive analysis of over 1200 patients in 25 countries. Rituximab maintenance is a common strategy for converting some partial responses to complete remission, and in others delaying disease progression, following initial treatment. It usually lasts two years and involves about 6-12 additional cycles of therapy. Cancer Care Ontario, for instance, funds eight maintenance doses over two years, or one every three months.
Once again, the PRIMA data show impressive progression-free survival statistics for follicular lymphoma patients -- meaning patients who, following treatment have both survived and experienced no further disease growth. 1217 patients were enrolled on the PRIMA study; after initial therapy with one of several rituximab-based regimens (R-CHOP, R-CVP, or R-FCM, which contains fludarabine), 1019 people with a detectable response were randomized to either untreated observation or to 2 years of rituximab maintenance.
The short-term benefits of rituximab maintenance are now very apparent. After the 2-year maintenance cycle was complete, 72% of patients were still in complete remission, compared with just over 50% in the untreated arm. Three years out, 75% of maintenance patients still had not experienced disease progression, compared with just 58% in the untreated group. This confirms other studies which suggest that rituximab maintenance cuts the relapse rate roughly in half over the short term.
What PRIMA can't yet answer is the increasingly urgent question of whether rituximab maintenance actually affects overall survival. Overall (long-term) survival statistics are a serious problem in indolent lymphoma research, because the natural history of the disease is already long enough that it can't easily be evaluated in a single trial. So far, the PRIMA data suggests no significant impact on overall survival. However, this may reflect the fact that 2- and 3-year survival statistics for follicular lymphoma are already so high that it is difficult to detect improvement. If benefits do exist, it may take a number of years for them to become apparent in the data.
Once again, the PRIMA data show impressive progression-free survival statistics for follicular lymphoma patients -- meaning patients who, following treatment have both survived and experienced no further disease growth. 1217 patients were enrolled on the PRIMA study; after initial therapy with one of several rituximab-based regimens (R-CHOP, R-CVP, or R-FCM, which contains fludarabine), 1019 people with a detectable response were randomized to either untreated observation or to 2 years of rituximab maintenance.
The short-term benefits of rituximab maintenance are now very apparent. After the 2-year maintenance cycle was complete, 72% of patients were still in complete remission, compared with just over 50% in the untreated arm. Three years out, 75% of maintenance patients still had not experienced disease progression, compared with just 58% in the untreated group. This confirms other studies which suggest that rituximab maintenance cuts the relapse rate roughly in half over the short term.
What PRIMA can't yet answer is the increasingly urgent question of whether rituximab maintenance actually affects overall survival. Overall (long-term) survival statistics are a serious problem in indolent lymphoma research, because the natural history of the disease is already long enough that it can't easily be evaluated in a single trial. So far, the PRIMA data suggests no significant impact on overall survival. However, this may reflect the fact that 2- and 3-year survival statistics for follicular lymphoma are already so high that it is difficult to detect improvement. If benefits do exist, it may take a number of years for them to become apparent in the data.
Monday, December 20, 2010
Protein Kinase Inhibitor: Enzastaurin
Protein kinase inhibitors are an experimental new class of drugs which are highly focused, targeting the enzymes which modify certain proteins, which in turn affect cancer growth. One such drug is Eli Lilly's enzastaurin, currently in clinical trials.
In a Phase II trial reported in 2010, 25% of 66 patients responded to the drug and another 40% had stable disease. Only 1 patient achieved complete remission. The duration of response was not reached when the study was published, with responses ranging (at that time) from about two months to almost two years.
Published Trial Results
L. Schwartzberg et al. "Enzastaurin in Patients with Follicular Lymphoma." Journal of Clinical Oncology (2010).
In a Phase II trial reported in 2010, 25% of 66 patients responded to the drug and another 40% had stable disease. Only 1 patient achieved complete remission. The duration of response was not reached when the study was published, with responses ranging (at that time) from about two months to almost two years.
Published Trial Results
L. Schwartzberg et al. "Enzastaurin in Patients with Follicular Lymphoma." Journal of Clinical Oncology (2010).
Mapatumumab: New Antibody for Follicular Lymphoma?
The clinical research field is currently awash with new treatments for follicular lymphoma and other forms of lymphoma. Most of these, of course, will not be marketed, either because they will turn out not to work at all or because they will not be noticeably more effective than alternative treatments. It's still too soon to say where mapatumumab will fit into this picture.
Mapatumumab is a monoclonal antibody drug -- an antibody designed to bind to a specific site on the surface of cells, in this case cancer cells. In this way it is similar to the better-known (and established) drug rituximab (Rituxan, MabThera), which is a standard drug in first-line treatment of follicular lymphoma. Where rituximab targets the CD20 protein, though, mapatumumab goes after a more novel target: Tumour Necrosis Factor-Related Apotosis-Inducing Ligand Receptor 1, Death Receptor 4 -- more simply, TRAIL-R1. Once it binds to that site, it triggers apoptosis -- programmed cell death, a genetic command to self-destruct after suffering damage which cancerous cells normally bypass.
Mapatumumab is a monoclonal antibody drug -- an antibody designed to bind to a specific site on the surface of cells, in this case cancer cells. In this way it is similar to the better-known (and established) drug rituximab (Rituxan, MabThera), which is a standard drug in first-line treatment of follicular lymphoma. Where rituximab targets the CD20 protein, though, mapatumumab goes after a more novel target: Tumour Necrosis Factor-Related Apotosis-Inducing Ligand Receptor 1, Death Receptor 4 -- more simply, TRAIL-R1. Once it binds to that site, it triggers apoptosis -- programmed cell death, a genetic command to self-destruct after suffering damage which cancerous cells normally bypass.
Treatment Options: Maintenance Treatment with Rituximab
Rituximab maintenance therapy typically involves multiple doses of rituximab given over a two-year period, such as at three-month intervals (for a total of eight doses in addition to whatever was given in initial treatment).
People who undergo rituximab maintenance have already responded to initial treatment. The premise behind the additional maintenance doses is that it may convert some partial responses into deeper (even complete) remissions, and that it should delay disease progression or relapse, since patients rarely relapse until at least after the maintenance round is complete.
The most important major clinical trial evidence supporting rituximab maintenance is an international study known as the PRIMA study (Primary Rituximab and Maintenance). PRIMA recruited over 1200 patients in 25 countries. 1019 people responded after initial treatment including rituximab (R-CHOP, R-CVP, or R-FCM) and then went on to the maintenance round. After three-years, progression-free survival was 75% in the maintenance arm, compared with 58% in the observation arm (who received no further treatment prior to progression).
Other studies have provided similar findings. The German Low-Grade Lymphoma Study Group reported in 2006 that the median progression-free survival after R-FCM was 16 months without maintenance, and had not reached the median in its maintenance arm.
Currently, the main question to be resolved is whether rituximab maintenance provides a genuine benefit in terms of overall survival. Indolent lymphoma life expectancies are long enough that overall survival studies take considerable amounts of time to complete. However, it is at least possible that the up-front benefit of maintenance is countered by greater resistance to therapy if and when relapse does occur, later on. Long-term studies are needed to confirm the benefits of rituximab maintenance.
People who undergo rituximab maintenance have already responded to initial treatment. The premise behind the additional maintenance doses is that it may convert some partial responses into deeper (even complete) remissions, and that it should delay disease progression or relapse, since patients rarely relapse until at least after the maintenance round is complete.
The most important major clinical trial evidence supporting rituximab maintenance is an international study known as the PRIMA study (Primary Rituximab and Maintenance). PRIMA recruited over 1200 patients in 25 countries. 1019 people responded after initial treatment including rituximab (R-CHOP, R-CVP, or R-FCM) and then went on to the maintenance round. After three-years, progression-free survival was 75% in the maintenance arm, compared with 58% in the observation arm (who received no further treatment prior to progression).
Other studies have provided similar findings. The German Low-Grade Lymphoma Study Group reported in 2006 that the median progression-free survival after R-FCM was 16 months without maintenance, and had not reached the median in its maintenance arm.
Currently, the main question to be resolved is whether rituximab maintenance provides a genuine benefit in terms of overall survival. Indolent lymphoma life expectancies are long enough that overall survival studies take considerable amounts of time to complete. However, it is at least possible that the up-front benefit of maintenance is countered by greater resistance to therapy if and when relapse does occur, later on. Long-term studies are needed to confirm the benefits of rituximab maintenance.
Bendamustine Continues to Impress
This month, some new trial data came available that continues to illustrate the advantages of the "new" alkylating agent bendamustine (Treanda). Bendamustine is a nitrogen mustard agent that was developed in East Germany in the 1960s. Despite being a very old communist drug, it is now a very new capitalist drug, with the price tag and brand name to boot. It's effective enough that there are now a number of trials looking at whether bendamustine can stand in for the more conventional chemotherapy regimens like CHOP (in combination, of course, with new drugs of choice like rituximab).
In Canada, there are currently five ongoing clinical trials involving bendamustine that are looking for test subjects with lymphoma. These include an ofatumumab trial in refractory patients (bendamustine versus O-B), a GA101 study in refractory patients (bendamustine versus B-GA101) the major BRIGHT Study for new patients (B-R going head to head with the older standbys, R-CHOP and R-CVP). A sixth trial is looking at bendamustine in childhood leukemia patients.
In Canada, there are currently five ongoing clinical trials involving bendamustine that are looking for test subjects with lymphoma. These include an ofatumumab trial in refractory patients (bendamustine versus O-B), a GA101 study in refractory patients (bendamustine versus B-GA101) the major BRIGHT Study for new patients (B-R going head to head with the older standbys, R-CHOP and R-CVP). A sixth trial is looking at bendamustine in childhood leukemia patients.
Saturday, December 18, 2010
An End to "Watch & Wait"?
"Watch & Wait" has got to be one of the stupidest phrases in medical history, guaranteed to provoke anxiety as much as any other response. The rationale is the same for all indolent lymphomas, like follicular lymphoma: decades ago, studies demonstrated that chemotherapy would have more or less the same effect whether it was started immediately upon diagnosis, or delayed until a later date when troubling symptoms developed or tumours grew to an unacceptable size. Since then, every new therapy is evaluated as a potential end to the watch and wait era.
Which brings us to Rituxan (rituximab), certainly the most important lymphoma drug of the last decade. One of the most important studies to emerge from the ASH conference in December 2010, judging from the flourish of congratulatory press coverage, is one claiming that rituximab is better with immediate, up-front treatment. So far, I'm just not buying it.
Which brings us to Rituxan (rituximab), certainly the most important lymphoma drug of the last decade. One of the most important studies to emerge from the ASH conference in December 2010, judging from the flourish of congratulatory press coverage, is one claiming that rituximab is better with immediate, up-front treatment. So far, I'm just not buying it.
Bexxar in Follicular Lymphoma
Along with Zevalin, Bexxar is one of two radioimmunotherapy agents effective against follicular lymphoma. In both cases, these drugs combine an anti-CD20 monoclonal antibody, similar to rituximab, with a radioactive isotope, in this case iodine-131.
Availability in Canada: Bexxar has been approved by Health Canada, but provincial funding is limited. Only the BC Cancer Agency has approved funding for Bexxar, and its protocol stipulates that the drug be used in a third-line setting. Bexxar has achieved success in trials in both treated and untreated patients; its use is reserved largely for cost reasons and because of existing effective first-line treatments.
How Bexxar Works:
Side Effects: Bexxar has very serious side effects.
Bexxar Monotherapy: One Bexxar monotherapy trial reported a 95% response rate (with 75% achieving complete remission) and median progression-free survival of 6 years.
Bexxar Combination Therapy: Clinical trial results have varied substantially, probably as a result of differing eligibility conditions. One trial combined Bexxar with CHOP, and found lower figures: a 90% response rate (with 67% entering complete remission), with 81% progression-free after 2 years. The most impressive figures come from a Bexxar-CVP trial, which had a 93% complete remission rate and a median progression-free survival of at least 8 years.
Published Studies
Mark S. Kaminski et al. "131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma." New England Journal of Medicine (2005).
Brian K. Link et al. "Cyclophosphamide, Vincristine, and Prednisone Followed by Tositumomab." Journal of Clinical Oncology (2010).
Oliver W. Press et al. "A Phase 2 Trial of CHOP Chemotherapy Followed by Tositumomab." Blood (2003).
Availability in Canada: Bexxar has been approved by Health Canada, but provincial funding is limited. Only the BC Cancer Agency has approved funding for Bexxar, and its protocol stipulates that the drug be used in a third-line setting. Bexxar has achieved success in trials in both treated and untreated patients; its use is reserved largely for cost reasons and because of existing effective first-line treatments.
How Bexxar Works:
Side Effects: Bexxar has very serious side effects.
Bexxar Monotherapy: One Bexxar monotherapy trial reported a 95% response rate (with 75% achieving complete remission) and median progression-free survival of 6 years.
Bexxar Combination Therapy: Clinical trial results have varied substantially, probably as a result of differing eligibility conditions. One trial combined Bexxar with CHOP, and found lower figures: a 90% response rate (with 67% entering complete remission), with 81% progression-free after 2 years. The most impressive figures come from a Bexxar-CVP trial, which had a 93% complete remission rate and a median progression-free survival of at least 8 years.
Published Studies
Mark S. Kaminski et al. "131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma." New England Journal of Medicine (2005).
Brian K. Link et al. "Cyclophosphamide, Vincristine, and Prednisone Followed by Tositumomab." Journal of Clinical Oncology (2010).
Oliver W. Press et al. "A Phase 2 Trial of CHOP Chemotherapy Followed by Tositumomab." Blood (2003).
About Zevalin in Follicular Lymphoma
Along with Bexxar, Zevalin (ibritumomab tiuxetan) is an important radioimmunotherapy agent which combines an anti-CD20 monoclonal antibody, similar to the better-known rituximab, with a radioactive molecule, yttrium-90. It has been shown to be effective both in relapsed and untreated follicular lymphoma.
Zevalin in Canada: Health Canada approved Zevalin in 2005. However, it contains radioactive agents and can therefore only be used in appropriately controlled settings. Currently, the BC Cancer Agency has authorized Zevalin as third-line treatment for follicular lymphoma. CancerCare Ontario has chosen not to fund Zevalin due to high cost. Other provinces are still reviewing the drug for cost-effectiveness.
How Zevalin Works
Side Effects
Zevalin Monotherapy
Zevalin Consolidation Therapy: Zevalin can also be used as part of a combination treatment. One American study examined first-line R-CHOP followed by Zevalin (consolidation), followed by rituximab (maintenance), in 55 patients. It is difficult to separate out the effect of Zevalin versus the other two components (which are highly effective on their own), but the initial complete remission rate was 89%. Three in five of these patients was still in remission after four years. The study noted that bone marrow involvement was a major factor: 17 of 32 responders with compromised bone marrow relapsed within four years, compared to just 5 of 22 Stage III patients.
Zevalin Combination Therapy
Published Studies
D.R. Mehta et al. "Phase II Study of Short Course CHOP-Rituximab Followed by 90-y Ibritumomab Tiuxetan." Journal of Clinical Oncology (2010).
Zevalin in Canada: Health Canada approved Zevalin in 2005. However, it contains radioactive agents and can therefore only be used in appropriately controlled settings. Currently, the BC Cancer Agency has authorized Zevalin as third-line treatment for follicular lymphoma. CancerCare Ontario has chosen not to fund Zevalin due to high cost. Other provinces are still reviewing the drug for cost-effectiveness.
How Zevalin Works
Side Effects
Zevalin Monotherapy
Zevalin Consolidation Therapy: Zevalin can also be used as part of a combination treatment. One American study examined first-line R-CHOP followed by Zevalin (consolidation), followed by rituximab (maintenance), in 55 patients. It is difficult to separate out the effect of Zevalin versus the other two components (which are highly effective on their own), but the initial complete remission rate was 89%. Three in five of these patients was still in remission after four years. The study noted that bone marrow involvement was a major factor: 17 of 32 responders with compromised bone marrow relapsed within four years, compared to just 5 of 22 Stage III patients.
Zevalin Combination Therapy
Published Studies
D.R. Mehta et al. "Phase II Study of Short Course CHOP-Rituximab Followed by 90-y Ibritumomab Tiuxetan." Journal of Clinical Oncology (2010).
Monday, January 4, 2010
Maintenance Treatment: Interferon-alpha
Interferon-alpha (IFN alfa) is an older cytokine drug used to fight various cancers. It is not a standard first-line drug in lymphoma at this point, but older trials did evaluate interferon alpha, including in a maintenance role. Today, maintenance therapy, when used, is usually based on rituximab (Rituxan, MabThera).
A 2010 Italian review of previous trials argued that IFN alfa might have some impact on overall survival in follicular lymphoma, but only when added to combination chemotherapy, and only at the cost of greater toxic side effects.
Published Trials
P. Baldo et al. "Interferon-alpha for Maintenance of Follicular Lymphoma." Cochrane Database Systematic Reviews (2010).
A 2010 Italian review of previous trials argued that IFN alfa might have some impact on overall survival in follicular lymphoma, but only when added to combination chemotherapy, and only at the cost of greater toxic side effects.
Published Trials
P. Baldo et al. "Interferon-alpha for Maintenance of Follicular Lymphoma." Cochrane Database Systematic Reviews (2010).
Friday, January 1, 2010
Common Chemotherapy Drugs for Follicular Lymphoma
Common Combination Regimens
- R-CHOP, formerly CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
- R-CVP, formerly CVP (Rituximab, Cyclophosphamide, Vincristine, Prednisone)
- R-FCM, formerly FCM (Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone)
- RICE, formerly ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide)
Cytotoxic Agents
Alkylating Agents - Bendamustine (Treanda), Chlorambucil (Leukeran), Cyclophosphamide (Cytoxan), Ifosfamide
Anthracenedione Agents - Mitoxantrone
Anthracycline Antibiotics - Doxorubicin/Hydroxydoxorubicin (Adriamycin)
DNA Repair Enzyme Inhibitors - Etoposide
Mitotic Inhibitors - Vincristine (Oncovin)
Platinum-Based Agents - Carboplatin
Purine Analogs - Fludarabine (Fludara)
Steroids - Dexamethasone, Prednisone
Monoclonal Antibodies
Anti-CD20 Antibodies - Bexxar (tositumomab iodine-131), Ofatumumab (Arzerra), Rituximab (Rituxan), Zevalin (ibritumomab tiuxetan yttrium-90)
New and Experimental Drugs for Follicular Lymphoma
Because lymphoma tends to be highly responsive to chemotherapy, it is a particularly rich and exciting area for new clinical research. There are currently a large number of potential new therapies winding their way through various stages of the preclinical and clinical trial cycle. Northoma's Canadian Clinical Trials page tracks clinical trials now occurring in Canada.
Experimental drugs that have failed to show benefit in Phase III trials are moved to the Drug Graveyard page. Drugs that are approved and pass into common use are listed on the Chemotherapy Drugs page. Results are often published in oncology journals - as a general rule, the more effective and promising the drug, the more high-ranked the journal.
Experimental drugs that have failed to show benefit in Phase III trials are moved to the Drug Graveyard page. Drugs that are approved and pass into common use are listed on the Chemotherapy Drugs page. Results are often published in oncology journals - as a general rule, the more effective and promising the drug, the more high-ranked the journal.
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