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http://www.clltopics.org/RituxanTherapy.htm
Bemærk problemer med resistens samt dårlige responses i refraktære patienter. 1. line ok resultater - men det vil Ofatumumab også vise !
Mechanism of Action
How Does Rituxan Work in CLL?
Date: January 3, 2003
by Chaya Venkat
This has been a topic of hot debate for the past few years, ever since this monoclonal antibody showed such dramatic results in the case of some types of non-Hodgkin's lymphoma, especially Follicular Lymphoma. The frustration for us has been that the results seems to be so much poorer for CLL patients, in earlier studies where this drug was used as single therapy. The results are somewhat better now. In this article I will try to summarize some of the more important trials, and also try to make sense of why the results are so different between some of them. We do not know all the answers yet, but the picture is getting clearer.
1. Initial studies with refractory CLL/SLL patients were disappointing. Only about 15% of the patients responded, when treated with the now standard dose of 375 milligrams/meter square (see a previous article about how to calculate body surface area or BSA, to find out what your particular dose would be), once a week for four weeks.
2. The effort was made to see if escalating the dose of the drug would improve the response rate (see first abstract below). The quantity of Rituximab administered was escalated from 375 mg/m2 (standard) all the way to 2,250 mg/m2. Infusion related toxicity was much more severe at the higher doses, as expected. However, even at 500 - 825 mg/m2, only about 22% of the patients responded, and the median duration of the response was only 8 months. Better than the 15% response rate seen before, but not much to write home about.
3. The first breakthrough came when Dr. Hainsworth looked at Rituxan as frontline therapy, i.e., in 'naive' patients that had not been subjected any therapy before. This study included NHL and SLL/CLL patients. The patients were a mixed bag, most of them in later stages. The standard 375 mg/m2 was used, once a week for four weeks, followed by the same amount once every 6 months as "maintenance" therapy, for a total of four sessions. The response rate with this approach was a whopping 70%, and the duration of the responses was also much longer, about 24 months. (see the second abstract below).
4. Now comes the last piece of the puzzle: Early stage CLL patients (stage 0, 1 and 2) were recruited, "naive" patients who had no symptoms, in no obvious need of therapy, with relatively low tumor burden. The only criteria was that they had beta-2-microglobulin higher than 2.0, classifying them as "high risk". (Between you and me, I think this was just a way to get the study going, a way to justify treating these patients in the first place. Labeling them as high risk patients must have made it easier to get around guidelines. Majority of patients have B2M higher than 2.0 at some point in their w&w period, with no obvious deterioration in their status).
In any case, getting back to our mystery, here is this group of very early stage, not at all sick CLL patients, and they received the standard dose, 375 mg/m2, once a week for 8 weeks. No infusion related toxicity to speak off, since the dose was the standard variety. Guess what, the response rate was a tremendous 90%, too early yet to say much about the duration of the response, but it is expected to be long. (See the third abstract below). What's more, recent studies have shown that patients can be re-treated with Rituxan, in fact the second time around the response duration can be even longer than the first time.
OK. Now let us see if we can get this straight. Refractory patients, who have already been through chemo, do not do so well on Rituxan alone. They are better off with one of the combo therapies, such as RFC (Rituxan, Fludarabine, Cyclophosphamide). It doesn't help much to just give them more of the juice, you run into toxicity problems at the higher doses, without really getting a whole lot more bang for the buck.
The key seems to be, using Rituxan as frontline therapy, in previously untreated patients. Hainsworth's study got a respectable response rate for the first time, for CLL patients, because he used only "naive" patients. But the real advantage came when Rituxan was used as frontline and single agent therapy in **early stage** patients, who had never been through therapy, in fact before they looked like they needed any therapy at all.
Now for some of the theories researchers have kicked around to explain the results. It was originally proposed that CLL cells exhibited lower number and concentration of the CD20 marker, compared to Follicular lymphoma cells. Since Rituxan locks on to the CD20 marker, this was proposed to be the reason for the poorer response. More detailed and careful studies showed that there was not a great deal of difference in the response of different patient groups that had different levels of CD20.
The next theory was that the CD20 marker sheds off the cancer cell and into the blood plasma more readily in the case of CLL than NHL. This free floating and junk CD20 was supposed to sop-up the precious Rituxan, tying it up and wasting it, so that in reality only a fraction of the drug actually got to the cancer cells. If this were the case, the dose escalation study should have shown sharp improvement in the response rates, because using this approach we were over whelming the free CD20 in the blood plasma. It was not the case. Another theory in jeopardy of being not quite the case.
Now we are beginning to understand better how Rituxan works, the pieces of the puzzle are coming together. Rituxan is not supposed to do a lot of the killing of the cancer cells by itself. As I wrote before, it is thought to lock on to the CD20 markers of the B-cells, and thereby make them attractive targets for killing. The actual killing is done by the other cells of the immune system, the t-cells, NK cells (natural killer cells), and others. Think of the Rituxan as collaring the b-cells, painting a big red "kill me" sign on them, making them more easy targets for the actual assassins. If you like jargon, the processes are called "antibody dependent cellular cytotoxicity" (ADCC) and "Complement dependent cytotoxicity" (CDC).
Problem is, while CLL patients usually have pretty good t-cell counts, except in special situations, for some reason the t-cells seem to get more and more compromised in their effectiveness as the disease progresses. It is as if the growing cancer cells are able to put out subversive propaganda, putting all the other cells of the immune system off guard. In fact, this is not a bad analogy, the cancer cells do put out chemical messages called cytokines that make the t-cells "anergic" or unable to function. The higher the tumor burden, the worse it gets. And in patients who have been through chemo already and refractory, the CLL cells left behind are even more adept at putting the t-cells to sleep.
OK, now we get it. In order for the Rituxan to work effectively as single agent, the patient must have an immune system that is still capable of functioning well, i.e., before the cancer burden has gotten out of hand, or before it has been traumatized by prior chemo. That is why the early stage, "naive' patients did so well in the last abstract below. And if the re-treatment is done before the CLL gets out of hand, the t-cell and NK cell populations are healthy, and able to do their jobs. Hence the good responses upon re-treatment.
Does this mean Rituxan is only for early stage and "naive" patients? By no means. If a patient has been through chemo, and there is reason to believe that his immune system cannot be counted on to be effective assassins and kill the b-cells tagged by the Rituxan, we can use other methods of killing, such as other chemotherapy drugs. That is why combos like RFC work so well. The Rituxan tags them, and the other two drugs kill them. It does not matter whether or not the rest of the immune system is up to snuff.
Down the road, we might be able to do better than that. Immune system not so good any more at killing Rituxan tagged b-cells? Not to worry, we will be able to grow huge armies of the patients own T- cells outside his body, train them to be efficient killers, and put them back into the body (see several articles in the archives on the subject of CTL therapy). Or we can use immunomodulatory drugs like Interleukin-2, which boosts t-cell production (see previous articles on this subject, combining Rituxan with IL-2, interferon alpha, GM-CSF etc.) Or we may come up with more effective ways of stimulating the immune system in-vivo, by approaches such as the "gene therapy" experiment now being conducted in phase - 2 trials at UCSD. The future looks bright indeed.
Sorry this got so long. But as you can see, it is a complex subject of great importance to us all, especially those in w&w and pondering future therapy choices.
Bemærk problemer med resistens samt dårlige responses i refraktære patienter. 1. line ok resultater - men det vil Ofatumumab også vise !
Mechanism of Action
How Does Rituxan Work in CLL?
Date: January 3, 2003
by Chaya Venkat
This has been a topic of hot debate for the past few years, ever since this monoclonal antibody showed such dramatic results in the case of some types of non-Hodgkin's lymphoma, especially Follicular Lymphoma. The frustration for us has been that the results seems to be so much poorer for CLL patients, in earlier studies where this drug was used as single therapy. The results are somewhat better now. In this article I will try to summarize some of the more important trials, and also try to make sense of why the results are so different between some of them. We do not know all the answers yet, but the picture is getting clearer.
1. Initial studies with refractory CLL/SLL patients were disappointing. Only about 15% of the patients responded, when treated with the now standard dose of 375 milligrams/meter square (see a previous article about how to calculate body surface area or BSA, to find out what your particular dose would be), once a week for four weeks.
2. The effort was made to see if escalating the dose of the drug would improve the response rate (see first abstract below). The quantity of Rituximab administered was escalated from 375 mg/m2 (standard) all the way to 2,250 mg/m2. Infusion related toxicity was much more severe at the higher doses, as expected. However, even at 500 - 825 mg/m2, only about 22% of the patients responded, and the median duration of the response was only 8 months. Better than the 15% response rate seen before, but not much to write home about.
3. The first breakthrough came when Dr. Hainsworth looked at Rituxan as frontline therapy, i.e., in 'naive' patients that had not been subjected any therapy before. This study included NHL and SLL/CLL patients. The patients were a mixed bag, most of them in later stages. The standard 375 mg/m2 was used, once a week for four weeks, followed by the same amount once every 6 months as "maintenance" therapy, for a total of four sessions. The response rate with this approach was a whopping 70%, and the duration of the responses was also much longer, about 24 months. (see the second abstract below).
4. Now comes the last piece of the puzzle: Early stage CLL patients (stage 0, 1 and 2) were recruited, "naive" patients who had no symptoms, in no obvious need of therapy, with relatively low tumor burden. The only criteria was that they had beta-2-microglobulin higher than 2.0, classifying them as "high risk". (Between you and me, I think this was just a way to get the study going, a way to justify treating these patients in the first place. Labeling them as high risk patients must have made it easier to get around guidelines. Majority of patients have B2M higher than 2.0 at some point in their w&w period, with no obvious deterioration in their status).
In any case, getting back to our mystery, here is this group of very early stage, not at all sick CLL patients, and they received the standard dose, 375 mg/m2, once a week for 8 weeks. No infusion related toxicity to speak off, since the dose was the standard variety. Guess what, the response rate was a tremendous 90%, too early yet to say much about the duration of the response, but it is expected to be long. (See the third abstract below). What's more, recent studies have shown that patients can be re-treated with Rituxan, in fact the second time around the response duration can be even longer than the first time.
OK. Now let us see if we can get this straight. Refractory patients, who have already been through chemo, do not do so well on Rituxan alone. They are better off with one of the combo therapies, such as RFC (Rituxan, Fludarabine, Cyclophosphamide). It doesn't help much to just give them more of the juice, you run into toxicity problems at the higher doses, without really getting a whole lot more bang for the buck.
The key seems to be, using Rituxan as frontline therapy, in previously untreated patients. Hainsworth's study got a respectable response rate for the first time, for CLL patients, because he used only "naive" patients. But the real advantage came when Rituxan was used as frontline and single agent therapy in **early stage** patients, who had never been through therapy, in fact before they looked like they needed any therapy at all.
Now for some of the theories researchers have kicked around to explain the results. It was originally proposed that CLL cells exhibited lower number and concentration of the CD20 marker, compared to Follicular lymphoma cells. Since Rituxan locks on to the CD20 marker, this was proposed to be the reason for the poorer response. More detailed and careful studies showed that there was not a great deal of difference in the response of different patient groups that had different levels of CD20.
The next theory was that the CD20 marker sheds off the cancer cell and into the blood plasma more readily in the case of CLL than NHL. This free floating and junk CD20 was supposed to sop-up the precious Rituxan, tying it up and wasting it, so that in reality only a fraction of the drug actually got to the cancer cells. If this were the case, the dose escalation study should have shown sharp improvement in the response rates, because using this approach we were over whelming the free CD20 in the blood plasma. It was not the case. Another theory in jeopardy of being not quite the case.
Now we are beginning to understand better how Rituxan works, the pieces of the puzzle are coming together. Rituxan is not supposed to do a lot of the killing of the cancer cells by itself. As I wrote before, it is thought to lock on to the CD20 markers of the B-cells, and thereby make them attractive targets for killing. The actual killing is done by the other cells of the immune system, the t-cells, NK cells (natural killer cells), and others. Think of the Rituxan as collaring the b-cells, painting a big red "kill me" sign on them, making them more easy targets for the actual assassins. If you like jargon, the processes are called "antibody dependent cellular cytotoxicity" (ADCC) and "Complement dependent cytotoxicity" (CDC).
Problem is, while CLL patients usually have pretty good t-cell counts, except in special situations, for some reason the t-cells seem to get more and more compromised in their effectiveness as the disease progresses. It is as if the growing cancer cells are able to put out subversive propaganda, putting all the other cells of the immune system off guard. In fact, this is not a bad analogy, the cancer cells do put out chemical messages called cytokines that make the t-cells "anergic" or unable to function. The higher the tumor burden, the worse it gets. And in patients who have been through chemo already and refractory, the CLL cells left behind are even more adept at putting the t-cells to sleep.
OK, now we get it. In order for the Rituxan to work effectively as single agent, the patient must have an immune system that is still capable of functioning well, i.e., before the cancer burden has gotten out of hand, or before it has been traumatized by prior chemo. That is why the early stage, "naive' patients did so well in the last abstract below. And if the re-treatment is done before the CLL gets out of hand, the t-cell and NK cell populations are healthy, and able to do their jobs. Hence the good responses upon re-treatment.
Does this mean Rituxan is only for early stage and "naive" patients? By no means. If a patient has been through chemo, and there is reason to believe that his immune system cannot be counted on to be effective assassins and kill the b-cells tagged by the Rituxan, we can use other methods of killing, such as other chemotherapy drugs. That is why combos like RFC work so well. The Rituxan tags them, and the other two drugs kill them. It does not matter whether or not the rest of the immune system is up to snuff.
Down the road, we might be able to do better than that. Immune system not so good any more at killing Rituxan tagged b-cells? Not to worry, we will be able to grow huge armies of the patients own T- cells outside his body, train them to be efficient killers, and put them back into the body (see several articles in the archives on the subject of CTL therapy). Or we can use immunomodulatory drugs like Interleukin-2, which boosts t-cell production (see previous articles on this subject, combining Rituxan with IL-2, interferon alpha, GM-CSF etc.) Or we may come up with more effective ways of stimulating the immune system in-vivo, by approaches such as the "gene therapy" experiment now being conducted in phase - 2 trials at UCSD. The future looks bright indeed.
Sorry this got so long. But as you can see, it is a complex subject of great importance to us all, especially those in w&w and pondering future therapy choices.
Husted siger der er et spænd mellem 9,4 måneder og ikke opnået, hvilket giver 13,7 mdr i gennemsnit. Har rituxan nogle ikke opnået. Der kunne opnås CR i den gruppe også!
vi er iøvrigt ikke langt fra hverken ash eller filing. Kan ikke forestille mig at stoffet ikke bliver godkendt nu. Det ser simpelthen for stærkt ud. Har du nogen data på om fda altid bruger 6 måneder på fast track? eller nogen gange går hurtige til værks?
12/11 2008 13:07 troldmanden 0196 Tror du vil ende med at blive skuffet hvis du begynder at regne med en godkendelse til april. Som jeg lige har skrevet så har FDA en hel del problemer med at overholde deres forpligtelser. Og når du regner på hvornår et reelt salg kan påbegynde så skal du også lægge ca 3 mdr oveni den dato hvor godkendelsen falder. For det tager ca den tid at få de sidste detaljer omkring produktion og sælger på plads inden den første recept kan udskrives. Så mit bud er omkring sep.
Noget helt andet er at det altså er en rigtig god ide stadig "kun" at indregne en 90% sandsynlighed for at stoffet kommer på markedet (i denne indikation). Der er set et HAV af stoffer som myndighederne vender tommelfingeren ned til. Også selvom alle regnede med en godkendelse. Det er ganske enkelt umuligt at forudsige hvad FDA gør. Og ja også cancer stoffer er blevet afvist selvom alle regnede med en godkendelse
Noget helt andet er at det altså er en rigtig god ide stadig "kun" at indregne en 90% sandsynlighed for at stoffet kommer på markedet (i denne indikation). Der er set et HAV af stoffer som myndighederne vender tommelfingeren ned til. Også selvom alle regnede med en godkendelse. Det er ganske enkelt umuligt at forudsige hvad FDA gør. Og ja også cancer stoffer er blevet afvist selvom alle regnede med en godkendelse
jeg regner faktisk 100% med at de bliver godkendt og det tror jeg også markedet gør. Her er mine begrundelser:
1. Det er et unmet medical need, dødssyge patienter uden anden behandlingsmulighed
2. Bivirkningsprofilen er god
3. 51/44% responsrate, herunder 1 complete
4. FDA har markeret at 20% responsrate var sikker
5. GSK har den bedste godkendelsesrate i hele medico branchen
1. Det er et unmet medical need, dødssyge patienter uden anden behandlingsmulighed
2. Bivirkningsprofilen er god
3. 51/44% responsrate, herunder 1 complete
4. FDA har markeret at 20% responsrate var sikker
5. GSK har den bedste godkendelsesrate i hele medico branchen
12/11 2008 13:51 troldmanden 0200 som nævnt så er der mange andre selskaber der har stået mere eller mindre i samme situation og fået et nej. Derfor mener jeg det er uklogt at indregne en 100% sandsynlighed. INTET er sikkert før fda har afsagt dommen. Jeg er overbevist om at ikke engang Lisa eller deres kliniske chef tør sige at det er 100%. Og jeg håber da så sandelig heller ikke at analytikerne har indregnet 100%. Så kan man reelt set kun blive skuffet. En godkendelse bør jo så rent faktisk ikke betyde noget for NPV da de allerede har indregnet det.....
ingen analytikere har indregnet det som 100% så vidt jeg ved, men jeg tror jeg har set en enkelt der har kørt den op til 95%. De har også kursmål 558 
12/11 2008 12:59 troldmanden 0195 Der har skam for år tilbage været godkendelser på helt ned mod 3 mdr. Men også gange hvor det har taget 8-9 mdr.
Der er desværre masser af eksempler på at FDA ikke kan overholde deres PDUFA deadline. Vi så det senest med Novos nye GLP1 antagonist Liraglutide hvor FDA ikke kan overholde tidsplanen.
Loven er også fleksibel skrevet idet den siger at 90% af alle fasttrack ansøgninger skal afgøres indenfor 6 mdr og 10 mdr med "normale" ansøgninger. Men som jeg forstår det så kan de ikke overholde den med de 90%.
FDA er vildt underbemandet og har bla ikke haft nogen chef i hmm mener det er omkring 1 år.
I denne tid er det stort set umuligt for selskaberne at få sat pre IND møder op med FDA. Det vil sige at selskaberne faktisk ikke har mulighed for at indgå i en dialog med myndighederne om hvorledes det/de kliniske forsøg i næste fase skal se ud og/eller om myndighederne har krav til f.eks flere prækliniske data inden de næste forsøg kan indledes. Derfor famler de fleste selskaber faktisk lidt i blinde i denne tid. De bruger både masser af tid (og lidt mindre grad penge) på at designe forsøg hvor de overhovedet ikke ved om det egentligt er tilfredfsstillende for FDA. Så derfor tror jeg godt man kan forvente at se mange flere IND ansøgninger ende med at blive afvist. Det bliver bare ikke kommunikret ud til markedet. I stedet undre folk sig bare over hvorfor det tager så lang tid at få startet den næst fase op
Der er desværre masser af eksempler på at FDA ikke kan overholde deres PDUFA deadline. Vi så det senest med Novos nye GLP1 antagonist Liraglutide hvor FDA ikke kan overholde tidsplanen.
Loven er også fleksibel skrevet idet den siger at 90% af alle fasttrack ansøgninger skal afgøres indenfor 6 mdr og 10 mdr med "normale" ansøgninger. Men som jeg forstår det så kan de ikke overholde den med de 90%.
FDA er vildt underbemandet og har bla ikke haft nogen chef i hmm mener det er omkring 1 år.
I denne tid er det stort set umuligt for selskaberne at få sat pre IND møder op med FDA. Det vil sige at selskaberne faktisk ikke har mulighed for at indgå i en dialog med myndighederne om hvorledes det/de kliniske forsøg i næste fase skal se ud og/eller om myndighederne har krav til f.eks flere prækliniske data inden de næste forsøg kan indledes. Derfor famler de fleste selskaber faktisk lidt i blinde i denne tid. De bruger både masser af tid (og lidt mindre grad penge) på at designe forsøg hvor de overhovedet ikke ved om det egentligt er tilfredfsstillende for FDA. Så derfor tror jeg godt man kan forvente at se mange flere IND ansøgninger ende med at blive afvist. Det bliver bare ikke kommunikret ud til markedet. I stedet undre folk sig bare over hvorfor det tager så lang tid at få startet den næst fase op
var der ikke noget med at de fik tilført flere ressourcer her for et år siden??
12/11 2008 13:54 troldmanden 0205 om det lige er et år siden kan jeg ikke huske. Men ved de stadig er massivt underbemandet. Både bava og NS fortalte også om de forværede adgangsmuligheder til myndighederne. Tesofensine fase 3 design er indsendt uden pre IND møder. Så derfor er der helt klart en forhøjet risiko for at fda siger ikke godt nok. Dit og dat skal laves om
