Cancer Treatment Reuiews (1988) 15 (&QQh&nt A), 5545

Discussion

CML/CGL

Question: You have mentioned that the blast crisis was more frequently lymphoid. Is that enhancement of lymphoid crisis and/or expression of myeloid?

Dr Talpaz: The overall survivals show there is no tremendous reduction. You don’t see a high risk of mortality in the first two years, so your suggestion is somewhat unlikely. However, sometimes I am puzzled by a patient who has an excellent hematological remission but goes into lymphoid blast crisis very quickly. So I cannot rule out that in 5% of the patients or so there is an acceleration of the process.

Question: Do patients who go into lymphoid crisis subsequently respond to vincristine and prednisone?

Dr Tulpaz: The answer is essentially yes. I should mention one interesting thing. It seems that lymphoid blast crisis is somewhat different from myeloid. In some patients it does not occur through evolutionary phases; it occurs abruptly and immediately like a rapid transition and in some of the patients after going back into remission, there is a surprising finding; they still have a normal residual stem cell and many of them have diploid cells post-remission with vincristine/prednisone.

Question: How long did the remissions last with vincristine/prednisone?

Dr Talpazz: Using vincrisinte/adriamycin with prednisone-the VAP protocol-the aver- age duration of the remission is less than a year but one patient had a very surprising remission. He was a high risk patient who went into lymphoid blast crisis after two years on interferon. At the time he had a very good hematological remission. He has now been in remission of blast crisis for three years.

Questioner: If that’s true it is significant because the normal history is that you go into blast crisis and vincristine/prednisone gives you, at best, two or three months, maybe six if you’re lucky.

Dr Tu~pa~: That means they are still exquisitely sensitive to chemotherapy, they have never been exposed to chemotherapy initially and at least one ofthe patients with lymphoid blast crisis mentioned had a prolonged remission of three years.

Question: Dr Talpaz, in patients that had a complete cytogenetic response with total disappearance of the Philadelphia chromosome, did you consider storing the marrow and possibly doing an autologous transplant?

Dr Talpaz: It is difficult because there is a considerable suppression so the quality of marrows that can be pooled and collected is bad, and you have to stop treatment probably for a month or two before you see recovery. Therefore, it might be a kind of self-defeating exercise; you might lose response. Also these patients do not relapse. Patients who have

03057372/88/15AOO55 + 11 $03.00/O

55 0 1988 Academic Press Limited

56 DISCUSSION

two consecutive complete cytogenetic responses have not relapsed so far and overall 1 have I5 such patients from all studies.

Dr Ocer: As you know, our prior approach to the therapy of CML was control and almc palliation for the chronic phase, rather than rigorous therapy. Dr Sokol now has data th if moderate dose ara-c and hydroxyurea are pushed in these patients to the point whe their B12 levels normalize and their white counts are much much lower than we wou have tolerated previously, they can get cytogenetic remissions as well. I’d like to ask bo our speakers on CML whether in fact what we are seeing is more aggressive therapy wi interferon, to the point where we are reducing the white count into the 24,000 range ar thus achieving cytogenetic remissions, and, had we pushed chronic chemotherapy to th point, whether we would have achieved the same results, or whether interferon really acting by a totally different mechanism?

Dr Talpaz: I want to relate to this question with perhaps an element of bias. When we SC cytogenetic remission without profound myelosuppression, (actually we see modera myelosuppression) it occurs when the white count is ranging between 2-5,000, and wonder whether you can get myelosuppression with interferon, even if you go to hue doses. Probably not. Only one patient, who had been previously exposed to mylera developed aplasia. Otherwise, patients can continue with very high doses of interfere and not develop myelosuppression. It seems that this selective effect occurs at a certai level when the count is between 224,000. It appears that the malignant clone does nc have a protective mechanism against the effect ofinterferon at this point, while the norm; stem cell is able to mount some kind of a defence. The evidence for that is also comin from solid tumor studies. You cannot indefinitely suppress the bone marrow with interfero and if you go to a melanoma study, for example, you will not see myelosuppressiot Actually, you will see an initial decline and then stabilization or return of the white coun and I think that that is the key mechanism; the ability of normal stem cell to protect itse against the suppressive regulation of interferon. We are now in the process of combinin low dose ara-c and interferon following the observation of Sokol. As far as I knol hydroxyurea has not been associated with stable or even temporary cytogentic response!

Dr Ozer: The old timers would immediately suggest that we never pushed hydroxyure hard enough to that white count.

Dr Alimena, at what level ofwhite count do you begin seeing your cytogenetic response> because you are giving a lower dose of interferon than Dr Talpaz?

Dr Alimena: We are also seeing the cytogenetic responses in patients with more thal 10,000 white blood cells/ml. We started to see cytogenetic improvement even in patient with partial hematologic response.

Dr OZer: Good cytogenetic responses in the order of 25% or more?

Dr Alimena: Response with Ph’-positivity not more than 50%; usually over 60-70% of Ph’ positivity and some of these patients have had only transient decline.

Dr OZer: I think that is a real discrepancy because in our CALGB study where we arc entering previously untreated patients, we are not seeing cytogenetic responses until after often 12 to 15 months of very prolonged therapy, and as Dr Talpaz is aware we begar treating with INTRON A at relatively low doses of 2 MU/m’, given seven days a week and those patients were slow to have a hematological response. After treating 16 patient!

DISCUSSION 57

we then increased our dose to 5 MU/m *. Whether they would ultimately have had a response we don’t know because we stopped entering at the lower dose, but it was quite clear that they were hematologically responding slower. I belive that the higher doses are required to achieve the most rapid and most significant hematological response in that the cytogenetic responses, in our hands at least, have been very delayed and only in patients who have had very significant hematological responses.

Dr Alimena: We have not seen the Ph’ decline before 5-6 months of treatment.

Dr Ozer: Dr Bergsagel perhaps has the model system for studying the maintenance question in CML and his study involves immediate reduction of the malignant cells and then institution of interferon therapy. How do you view this issue?

Dr Bergsagel: We have also seen cytogenetic responses with the low dose 2 MU/m*, three times a week. We have seen significant reductions in the proportion of Philadelphia- positive metaphases at five months. We have only seen one of six with cytogenetic response but it does occur with the lower dose. As with all other studies with interferon, it isn’t clear whether there is a dose-response effect for any disease, including CGL. Dr Talpaz has the strongest argument because he has the largest proportion of patients where the chromosome has disappeared, but, responses have been seen with lower doses. It may not be a dose-response question because Dr Talpaz administers the drug daily, and Dr Ozer will have administered the drug every other day as did Dr Madelli’s group.

An interesting theoretical question is that ifyou give interferon you get almost immediate down regulation of the receptor. So, if you assume that this occurs regardless of which interferon you use, but you use interferon on a daily basis, you may in fact be down regulating the receptor so much as to decrease the sensitivity of the cells as opposed to using it on alternate days. Down regulation lasts for a long period of time, 3 to 4 days, so why give additional interferon when there are no receptors on the cell surface to receive it?

Dr Talpar: We are not studying the target cells, we are studying the peripheral blood granulocytes which are not dividing cells and you do not know what is going on in the population of stem cells which form the proliferative pool in this disease.

Dr OZer: Dr Bergsagel, I would argue with your contention. We have looked in hairy cell leukemia at the target cells. In our in vitro and in uivo experiments, looking at type 1 receptors, when interferon is given in the very first dose to a patient who has a hairy cell leukemia, down regulation of receptors occurs immediately and is present at18 hours, but by 48 hours those receptors are regenerated both in vitro and in vivo; in vitro, in fact, within 24 hours. So the cell is clearly capable of regenerating its receptors on a relatively rapid basis.

With respect to the receptor issue, Dr Smyth, you mentioned other tumors and we know from in vitro work that breast cancer cell lines and colon cancer cell lines all have receptors for interferon. So, quite clearly, the lack of response in solid tumors to interferon is not due to the absence of a receptor. Do you have any evidence that there are any other mechanisms from the laboratory data?

Dr Smyth: Well I think you have almost answered the question. I think there is no doubt that the primary receptor for interferon on the cell surface does not correlate with response, but the problem is to identify the second messengers because there obviously is an ampli- fication phenomenon, and the second messenger is probably of far greater importance.

58 DISCUSSION

But most of the data on hematopoietic systems has been generated on Daudi cells and th Friend leukemia cell system and I am not aware of data that has been looked at in chroni granulocytic leukemia.

Dr Talpat: Actually we published in Cancer Research that two patients had been studiel at both stages, at the sensitive stage and the resistant stage. They have responded ts interferon initially and developed a resistance after a year or two in the benign phase Both had very similar receptor levels, studied by binding of labelled interferons. Ther was very similar binding at both stages and there was parallel down regulation of th receptors after 24 hours of exposure to interferon. However, in the sensitive phase thes patients induced very nice levels of the enzyme 2’5 iso-oligoadenylate synthetase. The did not induce any in the resistant phase. So whther that implies that the pivitol factor i the enzyme 2/5-A, or this is one of a series of other elements that are not induced, ant really the receptor is not internalized or whatever, it seems that it is beyond the initia step, i.e. the defect is beyond the binding.

Dr Smyth: What you clearly get with epithelial symptoms, for example, in breast cance cell lines, is an alteration in regulation ofother receptors, for example, the estrogen recepto is clearly induced by exposure to alpha-interferon, and obviously those sorts of mechanism may well result, particularly when we are looking at combinations of either cytotoxic drugs and interferons or combinations even of interferon-alpha and interferon-gamma and alpha-TNF and gamma-TNF. That interaction may clearly be very relevant.

Question: Dr Bergsagel, you said that during the evolution of chronic granulocytic leukemi: the leukocyte doubling time always shortens but I would like to know what happens ir those patients who get an acute crisis and then are reversed, lets say by high-dose con, ventional chemotherapy back to a second chronic phase. Would you say that in thi. instance the leukocyte doubling time shortens?

Dr Bergsagel: No, in those patients who enter an acute phase and are put back into the chronic phase, the leukocyte doubling time certainly will lengthen. During the acutt phase, the doubling time may be as short as one day, after they go back into the chronic phase it may lengthen to 30 to 40 days, but the progression starts again.

Or Tulpa~: I want to relate to Dr Bergsagel’s point on the shortening of the doubling time It is clear that CML is going through multiple evolutionary phases and, at least grossly, one of the manifestations is the increase of the rate of growth in these cells. However, 1 think that the evolutions of the disease do not always go linearly. I would say that in mosl of the myeloid blast crises that evolution is systematic; that means it’s kind of a longitudinal evolution. The disease goes through a decrease in doubling time, cytogenic evolution and blast crisis. However, as I have mentioned, in many of the lymphoid blast crises this is an acute, unpredicted event, that means you cannot always predict, with prognostic factors, the doubling time for this development. It’s kind of a one stage event rather than a multi- stage event.

DY Alimena: Dr Talpaz, was the blastic crisis of lymphoid type mainly seen in the non- responders or responders?

Or Talpaz: We have seen four patients who responded and progressed with blast crisis. Four of the 36 progressed not through a benign phase but through blast crisis directly. All

DISCUSSION 59

of them were lymphoid. Now we have seen blast crisis of the lymphoid among patients who never responded to interferon, we have seen myeloid and undifferentiated blast crisis.

Question: What should be the best schedule for treatment of CML in young patients in view of all these attractive, promising results?

Dr Talpaz: I maintain that what we are doing is clinical research and not purpose therapy at this point, but I assume it might turn to purpose therapy eventually. If a patient is a young male in his 20’s and he has a matching allogeneic donor, I think his first priority should be transplant, especially if he is intermediate/high-risk group. If he is in the low- risk group then I have some problems because he can do very well in four or five years rather than have problems from onset. Now if the patient is in the 30’s or 40’s, I would prefer to start with interferon. Here the risk, at least the published risk for transplant, is fairly high, and I think if he has a matching donor, I would go for 6-9 months on interferon. If he achieves hematological remission and starts to have a cytogenetic response, I would continue with interferon. If not, I obviously would go right away to transplant. In other words, I would delay the transplant. We have not demonstrated yet that interferon prolongs survival and thus this will only be demonstrated in randomized, controlled trials.

Dr OZer: I would make two modifications to that in my own perspective. My standard answer to that question in the United States is put your patient in a clinical trial. The evidence is very solid with hydroxyurea and busulfan that we’re not going to improve survival and, therefore, the incentive to enter a patient of any age into a clinical trial with interferon is very great. With respect to transplant, unequivocally allogeneic transplant can be life-saving in CML and there are now data in the United States from a number of centers demonstrating successful transplantation with minimal graft-versus-host disease in an allogeneic setting, up to the age of 45. Therefore, I would offer to my patient a transplant as an alternative, being aware that although you may be delaying his transplant in giving him four or five years of life with interferon therapy, we have no way of predicting the time of blast crisis. Your newly diagnosed patient may wind up in blast crisis at six months and, therefore, have lost the benefit for transplant in that setting.

Dr Talpaz: I would like to argue a little about the last point. Data from Donald Thomas shows a 50% survival (from the largest body of transplant data, at least in the U.S.A.) and 50% mortality in patients who have been transplanted above 40. As far as the very low mortality rate in allogeneic transplantation is concerned, I wonder if that includes T- cell purging and depletions where there is a very high relapse rate at the price of a very good initial response with low mortality.

Dr Bonnem: I want to make a comment about dose and response in CML. I think that there is too much emphasis here on an issue that really is a non-issue, because there is not much difference between 2 million and 5 million. If you talk about the difference between 2 million and 20 million, that’s a log difference, but the difference between 2 million and 5 million is not that great. My feeling is that what you should do is aim for a biologic effect. If 2 million is insufficient to bring the white count down, go to 5 million until you get a biologic effect, assuming that toxicity does not intervene. Do you agree Dr Talpaz?

Dr Talpaz: In CML I started with high doses, but at that time it was fairly empirical. Now we have some matched results from the studies of Drs Mandelli and Alimena and the CALGB studies, I would suggest a patient in CML, for example, to start with 2-3 MU/m2 three times a week. Those that do not respond, escalate the dose further because

60 DISCUSSION

I am sure that some will respond to the low dose and you will add a fraction of the patien who will respond to the higher doses. So this way you will simply not give too much 1 those that do not need so much. I am not sure as far as the quality and quantity ( cytogenetic response is concerned that this is not dose-dependent; this will have to L figured out later.

Lymphoma

Dr Ozer: Dr Chisesi, we are well aware of the activity of alpha-interferon in noduk lymphomas, do you have any experience or any thoughts about how, in the light 4 emerging data, we might apply alpha-interferons for other diffuse lymphomas (the higl grade lymphomas or Hodgkin’s disease) since there are data from phase 1 trials th; there is some activity?

Dr Chisesi: There are some phase 2 studies in low-grade NHL but the results are not E good; about 30% response. In Hodgkin’s lymphoma the percentage of response is lowe So many authors who have tried interferon in NHL are not in agreement to contim these studies.

Dr Ozer: But it would appear that data presented suggests that maintenance therapy wit interferon may have activity in myeloma, in hairy cell leukemia etc. and I wonder if regimen such as MACOP-B or MBCOD in high-grade lymphoma followed by mair tenance without the interferon would provide longer term remissions. Similarly, i Hodgkin’s if we alternated MOPP/ABVD with an interval of alpha-interferon or wit maintenance following 6 cycles, could we achieve prolonged remissions or a lower relaps rate in that patient population?

Dr Chisesi: Yes, theoretically, but the problem is where alpha-interferon acts biological1 because now we have responses in diseases where cells in the B-compartment differentiate hairy cell leukemia, Hodgkin’s lymphoma and low-grade NHL. In lymphomas like high grade or Hodgkin’s, the compartment of cells where alpha,-interferon should be is ver different from this disease and, therefore, biological effect should not be as active as i low-grade Hodgkin’s lymphoma or hairy cell leukemia where there is a compartment ( cells that can respond to the biological action of interferon.

Dr Oeer: So are you suggesting that the normal cells are responsible for the response i those patients, as opposed to a direct anti-proliferative effect?

Dr Chisesi: In differentiated versus normal cells, and in stimulated immunity when th mass of tumor is very low and is of cells that can respond to interferon. It is not the sam for high-grade or Hodgkin’s lymphoma where the tumor cell is completely different fror this compartment of cells.

Question: Following the very interesting biological experience that we look like we ar getting with CML I wonder if we would have an analogy with the follicular lymphomz as they also have a marker chromosome, like the 14, 18 translocation. Is there an experience regarding cytogenetic follow-up of patients treated with alpha-interferon wit regard to disappearance or modification of the cytogenetic abnormality?

Dr Ozer: There are no systematic data that I am aware of, although CALGB is now initiatin

DISCUSSION 61

studies in which they will look at 14-Q + abnormalities as well as bcl-2 abnormalities, bcl- 1 and cl1 . Data demonstrates activity for alpha-interferon in acute lymphocytic leukemia, and that is another situation in which cytogenetics and molecular studies would be particularly useful.

Dr Mandelli: As concerns acute lymphocytic leukemia, do you have any recent data regarding the use of interferon intravesically because there is some data, but in a very few patients, in which interferon was used for clearing liqor after meningeal abcess relapse?

Dr Ozer: The data in ALL that I am aware of is from the Pediatric Oncology Group at St. Judes and demonstrates that alpha-interferon is active as a single agent in a few percent of cases. In a relapse study in pediatric ALL, there are a significant number of responding patients to interferon as a single agent prior to rescue with chemotherapy. That is, a different strategy altogether; rather than using it as maintenance, it’s used initially for 10 days in relapsed patients and then following their given chemotherapy. In those patients, responses do not correlate necessarily with the presence or absence of type 1 receptors.

Dr Mandelli: Regarding acute lymphoblastic leukemia, I think that the dose of interferon is very high.

Dr Ozer: Yes, it requires high doses not low doses.

Dr Hofmann: Young adults and children can tolerate much higher doses than adults, that is important to know. Children can get away with 20 MU/m* daily probably.

Dr Oger: Similarly, with the pediatric lymphomas, higher doses can be given, and in that situation, it may be more applicable.

Question: Have you ever used interferon in acute lymphoblastic leukemia Philadelphia- positive? Also, do you use interferon and ara-c combined, and in which doses and schedule?

Dr Talpaz: Philadelphia-positive ALL is a very interesting situation. Molecularly it’s quite different from Philadelphia-positive CML. The break-point is probably outside the non- spanning area of the bcr. The chimeric protein, the product of the gene, is a different kind of protein. It’s a P190 and not a P2 10 and, maybe, this is the basis of the defect in regulation here. Several studies have been published, including our work on that subject. In Philadelphia-positive ALL we have not seen one responder. As you know, it is a bad disease with poor response on chemotherapy. So, situations that might superficially resemble as far a cytogenetics are concerned might be totally different on the molecular level. To the second question of ara-c. In our pilot study the doses that we use are those published by Sokol, 15 mg/m* daily continuous infusion or subcutaneously several times a day. He uses 2-3 weeks per course but we were unable to follow this schedule for such a long duration because ofthrombocytopenia; probably the course will be 1-2 weeks at most. We continued to use the maximal interferon dose, 5 MU/m’. The objective is to get as good a cytogenetic response as possible, i.e. to increase the fraction of complete cytogenetic response.

Hairy cell leukemia

Dr OZer: Dr Hofmann, where do we go from here with hairy cell leukemia? As you know we now have two active drugs; deoxycoformycin is also effective in inducing probably

62 DISCUSSION

complete remission hairy cell leukemia, and in the United States we have undertaken randomized study between deoxycoformycin and interferon in hairy cell leukemia. II Europe, and in your studies, what are you planning as follow-up?

Dr Hofmann: What we have to stress now is that with interferon, most probably, we canna obtain durable complete remission. It appears that remission can be obtained in a higl percentage of patients, but if we stop treatment, eventually relapse will occur. So we neec to know if deoxycoformycin can do more than interferon and, more importantly, whethe deoxycoformycin can be used in patients resistant to interferon which still is a problem I’m not yet in a position to judge deoxycoformycin.

Dr Ozer: We have initiated a trial with deoxycoformycin plus interferon for all hem atalogical malignancies. The rationale is that neither agent is myelosuppressive to a sever degree. Each has activity in one or another hematological malignancy and each may hav activity primarily in B-cell malignancies, which actually is surprising for deoxycoformycil which was designed as an anti-T-cell agent.

Dr Talpaz: I want to ask the people working with hairy cell leukemia a provocativ question. Is complete remission essential and important in hairy cell leukemia? I assum that most of the patients that relapse after stopping interferon will respond again t interferon. With a disease with such a low turnover, it is very unlikely that the disease wil develop resistance very quickly. So is the complete remission really an issue when perhap hematological remission is sufficient?

Dr Hofmann: I have written that I don’t believe that complete remission or the achievemen of complete remission must be the goal of treatment; it would be sufficient to obtain satisfactory blood levels of hemoglobin and granulocytes and so on. So you are right il that sense. I think one could consider hairy cell leukemia as kind of an interferon-deficien disease where you would have to substitute interferon on some basis, possibly one dos once monthly. We don’t know how little is just enough for this disease. Still, I am a littl worried, we don’t have any long-term follow-up. Even Dr Quesada may have only fou years’ follow up, and it is not known how long interferon can be given without som problems developing such as formation of antibodies, or something like that.

Question: Do we know the optimal dose of interferon in hairy cell leukemia?

Dr Hofmann: Well there are two questions. First, induction therapy? It has been shown b several authors that you may give much less than what we are giving. The proportion c response probably is the same but the speed at which you obtain remission may be longe if you give less, but eventually you will probably obtain the same number of remissions The second question is, what shall we do once we have achieved the goal we set? On’ strategy in the United States, as I understand, is to stop treatment and in some cases tc randomize nothing against chlorambucil.

Dr Ozer: Currently, we are essentially stopping treatment and following patients; restartinl them if they were previously responsive to interferon. Patients who become resistant or patients that are primarily resistant, receive either a splenectomy (if they are no splenectomized) or deoxycoformycin if they are.

Question: What is the dosing schedule for the use of the maintenance with interferon?

Dr Hofmann: There may be two strategies. Firstly stop treatment and determine a level a

DISCUSSION 63

which you would restart the patient. The second would be, and this is our own observation, that if you maintain the patient at a very low level, dosing every other week, that may just be sufficient. Either strategy may be valid and reasonable because patients who relapsed and were re-treated with interferon went into a comparable remission.

Question: You showed results following splenectomy where patients did respond well on interferon therapy; a favorable effect. Do you think that splenectomy still remains the first choice treatment in hairy cell leukemia?

Dr Hofmann: Actually I have changed my opinion from recommending splenectomy as the initial therapy towards the following recommendation. If a patient has significant cytopenia, to correct the cytopenia and then look at what happens with the spleen. If spleen size returns to normal then I think that no splenectomy is necessary. If the spleen size remains important, despite correction of the cytopenia, one may consider removing the spleen, but I have seen too many complications in patients primarily splenectomized with a severe cytopenia and I would prefer to correct the cytopenia before undertaking the splenectomy, which may not be necessary. In any case, I do not recommend a splenectomy in patients with normal spleen size.

Dr Ozer: Alpha-interferon in hairy cell leukemia is functioning essentially as a negative growth regulator. It is not a cytotoxic drug as we have come to think of standard cytotoxic drugs, thus it does not cure the disease but appears to control it for very prolonged periods of time, therefore, the areas of research that will be ofinterest in the future both with respect to hairy cell, and other malignancies, are whether resistance develops, how resistance might develop, whether positive growth factors are involved and needed to exert the negative growth influence (such as B-cell growth factor or interleukin 4) and, also from the clinical mechanistic point of view, as emphasized by Dr Hofmann, how to apply such things as negative growth regulators or alpha-interferons long term for clinical therapy. We have traditionally given it three times a week in the clinical trials that are ongoing throughout the world, it is stopped and the patients are given a therapy holiday and they relapse, not for many months, but it may be possible for example to give interferon on an intermittent basis in maintenance as Dr Hofmann has done, every week or two weeks or possibly even every month, single dose schedule. So those are things that I think will be areas of fruitful research in the future.

Multiple myeloma

Dr Ozer: Data suggests that similar strategies of application of interferon in maintenance therapy for the nodule lymphomas, for example, may be very relevant, and in keeping with the mechanisms theme again. But we are frequently faced with the choice of adding together two drugs as with chlorambucil plus interferon, cyclophosphamide plus inter- feron, platinum plus interferon, as opposed to sequential or maintenance therapy. It may be derived from maintenenace-type strategies.

Question: Dr Mandelli I should like to know if in the design of your study, there is a stratification for the kind of myeloma before the randomization of the patient?

Dr Mandelli: No, we stratify patients with respect to the type ofresponse after chemotherapy and we randomize the patient in the two different groups as concerns the previous

64 DISCUSSION

chemotherapy; melphalan and prednisone are most suitable for the chemotherapeuti schedule. But in the two groups the characteristics of the patients are very similar excer for the problem of more stage three in the arm without interferon.

Question: Did a patient who relapsed in the arm without interferon respond to subsequen treatment?

Dr Mandelli: Four or five of these patients responded to another chemotherapeuti approach, but this second-line chemotherapy is different from the first-line.

Question: I would like to ask whether this long remission duration translates into longe survival?

Dr Mandelli: It is impossible to answer your question because our study shows only th response duration and is not directed to evaluate the effect of interferon therapy regardini survival. But, our promising results could demonstrate in the future a real effect on surviva duration.

Question: When we clearly have to distinguish, it is biologically interesting to see that WI have prolonged remission duration but it is something different to have any benefit to the patient. Do you agree?

Dr Mandelli: Yes, it is of benefit to the patient to prolong remission. It is not only i biological effect.

Dr Ozer: That is true. I think the data are biologically intriguing, but to demonstrate efficacy, you must have improvement in survival. First of all a follow-up of these datz and then a prospective, randomized study giving optimum up front therapy followec by maintenance, would be required to confirm that.

Tolerance

Question: In our limited experience with interferon in multiple myeloma, older people art quite sensitive. Toxicity is quite high so how much effect would this have on the quality of life with these people? Do you think the cost-benefit analysis is for maintaining these patients on treatment?

Dr Mandelli: I think that it is important to use interferon at the low dose because in the first patient we had a very low tolerance and a problem with hematological toxicity. But 3 MU/m’, three times a week, is generally very well tolerated after the first week. It is important to convince the patient to continue with some kind of treatment. I think that this is the problem of all randomized studies.

DY OZer: Tolerance of long-term therapy is a very individualized issue with respect to an individual patient, an individual disease and an individual protocol. The patients on our CML protocol receiving 5 MU/ m2 daily, to my surprise are able to tolerate that very well for up to two years’ duration, with dose modification, often of 50% of the starting dose. Often, interruptions in therapy lead to a lot more toxicity when the therapy is restarted and that is due to the tachyphylaxis that patients do enjoy. Some of those patients are in the multiple myeloma age range. In addition, I think that combination with other agents such as in Dr Chisesi’s trial, leads to other toxicities such as myelosuppression that

DISCUSSION 65

might not have been appreciated by either giving chlorambucil or interferon. alone and so you have to individualize there. Finally, individual patients are very different. Some patients are completely intolerant of the most minor side-effects of interferon and other patients don’t even realize they are on a drug. In hairy cell leukemia we currently are running a trial of 500,000 U/m’, 3 times a week, as opposed to 2 MU/m’, and so we may not need ever again to experience toxicity, if that trial proves to be valid as the higher dose trial.

Question: What about the use of interferon in pregnant women with any kind of disease?

Dr Oeer: There has not been a systematic study of that particular issue. Dr Pentis from Italy and myself have experience of pregnant hairy cell patients. Both of these patients were 32, both were identified in their first trimester as having hairy cell leukemia and the coincidence of pregnancy. Dr Pentis’s patient had already been started on interferon therapy prior to the discovery of the pregnancy. My patient has not yet been started on interferon, although may very well need it or some other interventional therapy prior to delivery. Dr Pentis’s patient is now in the third trimester. It is a difficult issue and the teratogenicity studies from preclinical studies have not been well carried out and well characterized and I don’t think that we can base any rationale for treating these patients on known safety in a teratogencity situation. On the other hand, I think that the likelihood of significant damage to the child from interferon is rather low and I would certainly be willing, if pushed to it, to treat my patient with interferon, although I would presumably like to get her through her pregnancy without doing that.

Question: Dr Smyth, I think the results you presented with cisplatinum and interferon may be very interesting, but I would be concerned about a possible nephrotoxicity. Could you comment on that.

Dr Smyth: We have had no evidence of that in animal studies that you always get an increase in the therapeutic ratio, and in the clinical studies that are going on, both in Switzerland and the United Kingdom, there is no evidence that you potentiate the nephrotoxicity of platinum. Of particular interest to us, there is also no suggestion that you introduce myelotoxicity, which you were concerned with.