Transcript

Welcome to Updates from the 2007 Meeting of the American Society of Hematology (ASH) in the Management of Chronic Myeloid Leukemia (CML). Your faculty for this activity is Dr. Hagop Kantarjian, Chairman & Professor of the Leukemia Department at the University of Texas M. D. Anderson Cancer Center, in Houston, Texas. The question and answer session of this activity has been facilitated by Dr. Dean Buckner, founding member of the

Fred Hutchinson Cancer Research Center in Seattle, Washington.

Introduction

Dr. Kantarjian:I'm Dr. Hagop Kantarjian from MD Anderson Cancer Center and I am going to update you on some of the studies that were reported at the ASH 2007 [meeting].

Chronic myeloid leukemia (CML) is a proliferative disorder of the primitive hemopoietic stem cell. It is characterized by a chromosomal abnormality that we refer to as the Phildelphia chromosome because it was discovered in Philadelphia. This abnormality is associated with particular molecular events that we refer to as the BCR-ABL molecular abnormalities. These abnormalities are known to cause CML, based on the animal models in which the introduction of the BCR-ABL abnormality led to the recapitulation of the human CML disease in animals.¹ CML is a disease of older people with a median age of about 60-65 years and the  incidence in the United States today is about 5,000 cases per year.² However, since the mortality has been reduced from about 10-15% a year to less than 1-2% a year with the introduction of imatinib, the prevalence of CML is going to continue to increase until it plateaus to a level of about a quarter of a million cases in the United States.

Most patients with CML present in the chronic phase but there are about 10-15% of patients who present with accelerated or aggressive features that we refer to as accelerated phase CML. And a few of them will present with more than 30% immature cells or blasts and these are the cases that we refer to as blastic phase. Because of the routine screening of these patients, about half of them will have asymptomatic disease and the diagnosis will be made simply based on routine testing or routine physical exam. However, when there are symptoms they are mostly related to a high white cell count or to the development of splenomegaly- so many patients can present with fatigue related to anemia or to early satiety or left upper quadrant pains because of the splenomegaly.

I’m going to now give a brief overview of what was expected in the past and what will be expected today since the introduction of imatinib mesylate therapy. So as a historical perspective, patients who were diagnosed before the year 2000 were told that their course would be fatal, that their average survival was about 3-5 years, that their frontline therapy would be allogeneic SCT, when possible, which is curative but may be associated with mortality and with some morbidities.³ And if they progress on allogeneic transplantation or on interferon-based therapy then there were no acceptable second-line treatment options. Since the year 2000, when we see patients with CML we tell them that their prognosis should be excellent, and that their average survival should be in excess of 25-30 years. Certainly we know for a fact that their estimated 5-year survival would be [approximately] 90%. The frontline therapy for these patients will be with imatinib mesylate which is a BCR-ABL selective tyrosine kinase inhibitor (TKI), or a form of targeted therapy. If the patients progress on imatinib mesylate, then they have the option of using some of the more potent second-generation TKIs, like dasatinib or nilotinib, which are both FDA approved and commercially available, or they could opt for an allogeneic transplant which has an historical track record of a cure rate of 50% or more.

Unresolved Questions in CML

Now that imatinib mesylate therapy is frontline therapy for CML, there are several questions that need to be answered, I'm going to list them and give a brief answer to these questions and then elaborate on them in the subsequent portion.

• The first question is, how durable are imatinib-maintained responses? As of today with a follow-up time of about 6 years, we know that over 80% of the patients who receive imatinib continue to receive the treatment and are in a complete cytogenetic response (CCyR).
• Another question is how long should we give imatinib mesylate therapy and can we stop the treatment in patients who achieve a CCyR or a complete molecular response? As of today we advise patients to continue the treatment indefinitely because among the anecdotal patients who stop therapy- most of the patients had recurrence of their disease.
• Another question is [what is] the appropriate dose of imatinib therapy for initial treatment? While there have been a lot of discussions about standard dose imatinib 400 mg/day or a high-dose imatinib of 800 mg/day, currently the standard of care in newly diagnosed patients with CML would be imatinib 400 mg/day.
• The fourth question is what are the current treatment options for patients who fail on imatinib therapy and how do we define failure to imatinib therapy? There has been a group of experts that attempted to precisely define failure to imatinib therapy, and they defined failure as either
  • lack of achievement of a complete hematologic response (CHR) after 3 months,
  • no cytogenetic response (CyR) after 6 months,
  • a minor CyR or less after 12 months, meaning the Ph chromosome positivity is more than 35%,
  • any persistent chromosomal abnormality in the 2nd year, so lack of achievement of a CCyR, or
  • any progression or relapse at any point and time in the course of the  disease.

These are very strict criteria that allow patients to know that they have not responded to imatinib therapy and should look into the choice of second-line strategies such as the second-generation TKIs or allogeneic SCT. Now what are the options for therapy?, These would include dasatinib or nilotinib, which are approved treatments for imatinib failures, and new investigational approaches with novel TKIs or with forms of chemotherapy like decitabine, which is a hypomethylating agent, or HHT, which is one of the oral chemicals that has shown activity in CML.

• Another question is the effect of imatinib in the very elderly.  We know that the median age of CML is about 60-65 years,  and studies have shown that imatinib therapy appears to provide equivalent efficacy in elderly and younger patients in terms of response rates and survival.
• And finally a question regarding the use of allogeneic transplant in the setting of imatinib failure. The simple answer is that today perhaps most experts agree that allogeneic transplant should not be used as frontline therapy despite its curative potential because of the associated mortality and morbidity, and that it should be used as either a second- or a third-line strategy in patients who fail imatinib in transformation or in patients who fail imatinib in chronic phase who may benefit from the second- generation TKIs. 

ASH Data: IRIS Study

I'm going next to discuss some of the updates from ASH regarding initial therapy of CML. It was important to present the update of the international study of interferon versus STI571[imatinib mesylate] which we refer to as the IRIS trial. This is the original trial that randomized patients with newly diagnosed CML to imatinib versus interferon-based therapy. That study showed the superiority of imatinib therapy but there were questions remaining as to the long-term benefit.

The current 6-year update in over 500 patients using an imatinib dose of 400 mg/day has shown an estimated 5-year survival rate of about 90% and has shown that at 5-years, close to 80% of the patients continue on imatinib therapy and are in a CCyR.⁴

Another question [addressed at] the ASH meeting was whether patients who achieved a later CyR would have worse outcome.  A study from professor Guilhot in France looked at the outcome of 447 patients with CML on the IRIS trial who were treated for 1 year on imatinib therapy.⁵ What they show in this study is that in fact the time to achieving a CCyR was not associated with any differences in overall survival, EFS, or PFS. So the only patients who did poorly were the patients who never achieved a CCyR. This suggests that in our current practice we should be patient and continue the patients on therapy even if they don't achieve an early CCyR, because even if they achieve a CCyR after one and a half years, their outcome appears to be as good as the patients that achieve an earlier CCyR.

Now there were, of course, questions related to this analysis because some investigators said that there are many patients who fail earlier on and [who] are not accounted for by this analysis. There was also a question as to how many patients had received a dose escalation of imatinib to achieve a CCyR. So there are some unresolved issues as to when to move from standard-dose imatinib therapy to either high-dose imatinib or second-line treatment strategies once we are confident that the response to imatinib is suboptimal or incomplete.

ASH Data: Are higher doses of imatinib more effective?

Another question addressed at the ASH [meeting] is the use of high-dose imatinib therapy. This question has been addressed in many studies and most of them had shown that the higher dose of imatinib can overcome resistance to standard-dose imatinib and that patients with newly diagnosed CML who receive high-dose imatinib have higher and faster rates of major and complete remissions both at the cytogenetic and the molecular level.

There was an update from the IRIS trial in 106 patients who received imatinib dose escalation because of either failure by the approved standard criteria for imatinib-failure or because of suboptimal response.⁶ And what this analysis has shown is that among the patients who fail because of a cytogenetic relapse or an insufficient cytogenetic response, a dose escalation of imatinib can produce CCyRs which are durable.

However, when we use the dose-escalation of imatinib among patients who have hematologic resistance, then the responses with the high-dose escalation are either brief or suboptimal or of poor quality. So today our standard approach is for patients who have a  CyR but which is incomplete or which is unfavorable, then, a dose escalation of imatinib may produce durable CyRs.  But among patients who fail at the hematological level with hematologic resistance, dose escalation of imatinib provides only brief remissions and may not be sufficient.

ASH Data: Imatinib in Elderly Patients

There was also a study by Dr. Rohrbacher at the ASH meeting that looked at the use of imatinib therapy in patients who are elderly.⁷,⁸ The background of this study is that the median age of patients who participate in clinical trials is about 45-55 years, but from the SEER data the median age of CML patients  is reported to be closer to 65-70 years. So it was important to know whether in the community practice imatinib is being used commonly and whether it produces results similar to what is obtained in the younger patients. So the investigators reported on 30 patients with newly diagnosed CML whose age was 70 years or older, and they found that there was a high incidence of sustained CCyR in these patients similar to that obtained among the younger patients. However, they did notice 2 patients that developed CHF and the authors conclude that among patients with CML, imatinib therapy should be front line treatment regardless of  age, but we should be cautious among the very elderly patients who have congestive heart complications, because these may be the patients who are susceptible to the development of fluid retention and congestive heart failure.

Approved Second-Generation Tyrosine Kinase Inhibitors

Both of these [dasatinib and nilotinib] agents have already been approved for the treatment of CML in all phases following imatinib failure. And these agents have different spectra of toxicity that we have to be cognizant of. So one of the questions is what are the differences between the two agents?

First of all we know that dasatinib is a highly potent orally active inhibitor of both Src as well as BCR-ABL and it also is a potent inhibitor of c-Kit, which may explain some of the myelosuppression associated with the drug.  It also inhibits platelet derived growth factor receptor (PDGFR) which many investigators believe may be related to the incidence of pleural effusions.⁹,¹⁰,¹¹ This agent is 325 times more potent than imatinib and in the pre-clinical models it has been reported to be very potent; it  suppresses most of the mutants which cause resistance to imatinib except for one particular mutation referred to as T315I. As a background, when patients develop resistance to imatinib  we can detect mutations in 40% of them which explain the resistance to imatinib therapy.

Nilotinib, on the other hand, does not affect Src; it is a pure or selective BCR-ABL inhibitor. It's about 30-50 times more potent than imatinib and it was rationally designed with modifications of the attachment sites of imatinib outside the critical ATP binding structure to make the drug fit more selectively into the ATP-binding pocket and therefore be more potent.¹² Similar to dasatinib, it has been found to be highly effective in pre-clinical models and to be effective against all the BCR-ABL mutants except the T315I.

I'm going to start by detailing some of the studies that were reported with these two agents in different phases of CML. One of the questions was, if we have patients who receive second-generation TKIs  can we predict the responsiveness to these agents.

There was a study reported by Dr. Elias Jabbour from MD Anderson Cancer Center that looked at 120 patients who received either dasatinib or nilotinib following failure of imatinib therapy.¹³ And what the investigators reported is that the best predictor for the outcome of patients on 2nd generation TKIs was their response to initial imatinib therapy. So if the patients had achieved any CyR with imatinib therapy, they were more likely to achieve a 2nd durable CCyR and to have a favorable long-term outcome.

A second study, which I reported was the use of second-line dasatinib therapy in patients who fail imatinib therapy. The question that we addressed was the outcome of the patients by whether they received dasatinib at the time of a cytogenetic relapse or failure or at the time of hematologic relapse or failure.¹⁴ What we found in that study was that the patients who received dasatinib at times of cytogenetic relapse had much more favorable outcome than the patients who received the treatment at the time of hematologic relapse. This study suggested that earlier intervention with dasatinib or with a second-generation TKI will give better results and indicated the need for close monitoring of patients on imatinib therapy to detect the early cytogenetic relapse for early interventions. This is important in our community practice because some oncologists have decided not to monitor cytogenetic studies but to rely on hematologic relapse to intervene with the second-generation TKIs. The study which we reported argues that in fact we need to continue monitoring the patients with cytogenetic analysis at frequent intervals if we want to intervene with the second-generation TKIs in the best way we can.

There was also a study that compared dasatinib versus high-dose imatinib in patients with CML who were resistant to standard dose imatinib.¹⁵ In this study there were 150 patients who were randomized 2:1 to receive either dasatinib 70 mg orally twice a day or high dose imatinib at 800 mg orally twice a day. In that study, the long term data show that dasatinib therapy provides superior rates of CCyR as well as superior rates of complete molecular responses and event free survival (EFS) compared to high-dose imatinib therapy. This study tells us that today in patients who fail imatinib we have multiple treatment options which include high-dose imatinib, dasatinib, or one of the other second-generation TKIs.

Another study that was reported was the use of dasatinib in patients with CML in AP following imatinib failure.  In this study, among 174 patients with imatinib resistance or intolerance who were in AP,  the updated analysis at 2 years showed that there was a high response rate as well as a reasonable 2 year event free survival.¹⁶

There was also a study that reported on the use of nilotinib following imatinib failure in patients with CP CML. The study included 320 patients who received nilotinib 400 mg orally twice a day for the duration of their responsiveness.¹⁷ In that study, we were able to report a major CyR in about 50% of the patients, which was complete in about 40% of the patients. When we looked at the survival rates at 12 and 18 months, they were very favorable at the rate of 90 and 80%, respectively.  This suggests that the survival of the patients on 2nd generation TKIs following imatinib failure has already improved compared with our historical experience.

Dr. Phillip Le Coutre from Europe reported on the pivotal trial of nilotinib in CML in AP.  The report was on 119 patients who received  nilotinib 400mg orally twice a day with a potential dose escalation if they had failed imatinib therapy and showed signs of disease acceleration.¹⁸ That study also showed a significant rate of hematologic responses as well as cytogenetic responses in about 40% of the patients, which were durable.

ASH Data: Second-Generation TKIs in Newly Diagnosed CML Patients

There were two reports at ASH on the new generation TKIs in newly diagnosed patients with CML, and both of these were pilot single- institution studies from MD Anderson Cancer Center.

In the first study we treated patients with newly diagnosed CML with dasatinib at a total daily dose of 100 mg/day given either as a single daily dose or as 50mg orally twice a day.¹⁹ What we found with this treatment is a very rapid induction of CCyR in the large majority of patients with CML. So in fact close to 100% of the patients that received dasatinib achieved a CCyR by 6 months of therapy compared to lower rates of about 50-80% with the standard or the high-dose imatinib. So at this early stage we have reported that dasatinib provides superior and faster rates of CCyR in newly diagnosed CML compared to imatinib at the standard or the high-dose. Whether this will translate to a long-term survival or EFS benefit remains to be elucidated with longer-term follow up.

Another study that was conducted at our institution evalutaed nilotinib in 32 patients with newly diagnosed CML treated with nilotinib 400 mg orally twice a day.²⁰ Again, as with the dasatinib experience, close to 100% of the patients achieved a CCyR by 6 months of therapy and in both studies those responses were durable.   It is only the rare patient who had to discontinue therapy because of either progression or resistance. The survival rate with short-term follow up remains close to 100%.  These two frontline studies suggest that the newer generation TKIS are going to be very active. But the real question is whether the added toxicities will counterbalance the efficacy that we are seeing in the early results.

ASH Data: Other Novel TKIs

So I have already discussed 2 of the 2nd generations TKIs; dasatinib and nilotinib, one of them is dual SRC-Abl inhibitor and the second one is a selective BCR-abl inhibitor.  Both of them have shown high efficacy rates producing durable remissions in patients who have failed imatinib therapies. The third novel agent is also a Src-Abl inhibitor referred to as bosutinib or SKI606.  Studies evaluating this agent are ongoing and are almost complete in the setting of imatinib failure.²¹ The early trials are showing results equivalent to those achieved with dasatinib and nilotinib, and we are not yet seeing the problems of myelosuppression or pleural effusions. Therefore I believe that bosutinib or SKI606 is going to be the 4th TKI that may hopefully soon gain FDA approval for the same indication.

There is also a fourth agent called INNO-406 which is a SRC- ABL inhibitor. A completed Phase I trial demonstrating very encouraging data and safety at a dose of 200 mg orally twice a day has been reported.  We have already taken INNO-406 into phase II studies.²² 

Conclusion

In summary, I believe that the outcomes of patients with CML are outstanding. With the existing treatments we can expect most of the patients to lead normal lives. There remains the unanswered question of whether we can stop therapy? Several investigators are working on immune modulatory strategies or on chemotherapy strategies in minimal residual disease to try to eradicate the disease and stop the treatment and not only provide a functional cure but a molecular cure as well. Among the patients who have progressive disease there are multiple treatment options which are available that hopefully [will] further improve their prognosis.

That concludes Dr. Kantarjian's presentation on Updates from ASH 2007 on Chronic Myeloid Leukemia. Please click here to view the question and answer session with Dr. Buckner and Dr. Kantarjian.

Question and Answer Session

Dr. Buckner: Can patients in long-term molecular remission discontinue their imatinib?

Dr. Kantarjian:  This is in important question that we don’t have an answer for today. There was a study by Dr. Rousselot from France in which 16 patients who were in complete molecular remission for at least 2 years stopped therapy.²³ And what was found was that half of the patients had molecular relapse within two years but the other half continued to be in a complete molecular response for at least a year. So today we advise all patients to continue imatinib therapy indefinitely. But it is possible that in the future, with more information, we’ll be able to know in which patients we can stop therapy and not have a molecular relapse.

Dr. Buckner: Can imatinib be given safely to pregnant women?

Dr. Kantarjian: At this stage what we know is that in women with CML who were on imatinib therapy and who became pregnant, we stopped the imatinib therapy and most of the patients continued to a normal delivery with normal babies.²⁴ Today we do not advise any women with CML on imatinib therapy to continue imatinib throughout the pregnancy because we do not know the effects of imatinib therapy on the child and the normal development.

Dr. Buckner: Can you define the definition of treatment failure on imatinib?

Dr. Kantarjian: We define treatment failure on imatinib in a patient who does not achieve a CHR after 3 months of therapy or in a patient who does not have any cytogenetic response after 6 months of therapy.²⁵ [Other treatment failures include] patients who do not have a major molecular response or better at 12 months, so the Philadelphia is 35% or more; patients who are into their second year and continue to have Philadelphia positivity, so patients who are not into a CCyR into their second year;   and finally, patients who relapse or become clear-cut resistant at either the cytogenetic or the hematologic levels. These are the current definitions of imatinib failure that we use to change therapy to a second generation TKI.

Dr. Buckner: Can you outline the optimal monitoring methods with cytogenetics and PCR (polymerase chain reaction) for patients being treated with imatinib?

Dr. Kantarjian: Today we have 3 tools to monitor the patients.²⁶ Cytogenetics is the standard, but it’s done on the bone marrow, which is painful. The FISH analysis can look at 200 metaphases, so they are more precise, and we can do them on the blood. And finally the molecular monitoring with what we call quantitative PCR.²⁷ At our institution, in patients who are not on protocol we try to do the bone marrow once a year, including the cytogenetics, and we alternate the other 6 months with FISH analysis and qPCR. So we do the qPCR in a patient in a stable CCyR only once every 6 months, rather than what [others]  have advocated, which would be a qPCR every 2-3 months. We think this is an overuse of the molecular analysis and in fact in a patient in a CCyR we should not jump the gun for variations in the molecular level because these in our experience have not predicted for a difference in survival. So while there are molecularly enthusiastic people who want to do qPCR studies very frequently, we feel that in a patient in a stable CCyR, monitoring the molecular data frequently may not give us additional useful information.

Dr. Buckner: Could you tell us when you look for mutational abnormalities by PCR?

Dr. Kantarjian: Again, I think there is an overuse of the mutational analysis.  I do not believe in our current practice that we should do mutational studies in either pre-treatment or in a patient who is responding. However in a patient who has cytogenetic or hematologic relapse, it is important to do the mutational analysis because it can select out the patients with the occasional T315I mutation who will not benefit from the 2nd generation kinase inhibitors but who may benefit from undergoing an allogeneic transplant as soon as possible. Also there are certain mutations which may be more responsive to one TKI versus another. So the mutational studies are very important, but only in the setting of a patient who is exhibiting clear-cut cytogenetic or hematologic failure.

Dr. Buckner: Dr. Kantarjian; thank you very much for this expert presentation.

Dr. Kantarjian: Thank you for inviting me. 

¹ Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207-19.

² Cancer Facts & Figures 2007.

³ Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.

⁴ Hochhaus A, Druker B, Larson R, et al. IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Program and abstracts of the 49th Annual Meeting of the American Society of Hematology; December 8-11, 2007; Atlanta, Georgia. Abstract 25.

⁵ Guilhot F, Larson RA, O’Brien SG, et al. Time to complete cytogenetic response (CCyR) does not affect long-term outcomes for patients on imatinib therapy. Blood. 2007;110:16a, Abstract 27.

⁶ Kantarjian H, Druker B, Guilhot F, et al. Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP). Program and abstracts of the 49th Annual Meeting of the American Society of Hematology; December 8-11, 2007; Atlanta, Georgia. Abstract 1047.

⁷ Rohrbacher M, Berger U, Hochhaus A, et al. Clinical trials underestimate age of chronic myeloid leukemia (CML): Epidemiological study in a representative area in Germany. Blood. 2007;110:868a, Abstract 2955.

⁸ Rousselot P, Nicolini F, Mahon FX, et al. High efficiency and particular safety profile of imatinib mesylate (Glivec®) in elderly patients with CML in chronic phase: Results of the AFR04 prospective study. Blood. 2007;110:315a, abstract 1039.

⁹ Das J, Chen P, Norris D, et al. 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem. 2006;49:6819-32.

¹⁰ O'Hare T, Walters DK, Stoffregen EP, et al. Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res. 2005 Oct 1;11:6987-93.

¹¹ Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004 Jul 16;305:319-21.

¹² Cowan-Jacob SW, Guez V, et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem. 2004 Mar;4:285-99.

¹³ Jabbour E, Kantarjian H, Shan J, et al. Prognostic significance of prior best response to imatinib in patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) treated with second generation tyrosine kinase inhibitors (TKI’s). Blood. 2007;577, Abstract 1942.

¹⁴ Kantarjian HM, Quintas-Cardama A, O’Brien S, et al. Importance of early intervention with dasatiib at cytogenetic rather than hematologic resistance to imatinib. Blood. 2007;110:314a, abstract number 1036.

¹⁵ Kantarjian H, Rousselot P, Pasquini R, et al. Dasatinib or high-dose imatinib for patients with chronic phase chronic myeloid leukemia resistant to standard-dose imatinib: 2-year follow-up data from START-R (CA180-017). Blood. 2007;110:226a, Abstract 736.

¹⁶ Francois Guilhot, Jane F. Apperley, Dong-Wook Kim, et al. Efficacy of Dasatinib in Patients with Accelerated-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-A (CA180-005). Blood. 2007;110:145a. Abstract 470.

¹⁷ Kantarjian HM, Hochhaus A, Cortes J, et al. Nilotinib is highly active and safe in chronic phase chronic myelogenous leukemia (CML-CP) patients with imatinib resistance or intolerance. Blood. 2007;225a. Abstract 735.

¹⁸ Le Coutre P, Giles FJ, Apperly J, et al. Nilotinib is safe and effective in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib resistance or intolerance. Blood. 2007;145a. Abstract 471.

¹⁹ Cortes J, O’Brien S, Jones D, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood. 2007;110:17a, Abstract 30.

²⁰ Cortes J, O’Brien S, Jabbour E, et al. Efficacy of nilotinib (AMN107) in patients (pts) with newly diagnosed previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood. 2007;17a. Abstract 29.

²¹ Cortes J, Bruemmendorf T, Kantarjian H, et al. Efficacy and safety of bosutinib (SKI-606) among patients with chronic phase PH+ chronic myelogenous leukemia. Blood. 2007;225a. Abstract 733.

²² Kantarjian HM, Cortes J, le Coutre P, et al. A phase I study of INNO-406 in patients with advanced Philadelphia (PH+) chromosome-positive leukemias who are resistant or intolerant to imatinib and second generation tyrosine kinase inhibitors. Blood. 2007;110:144a. Abstract 469.

²³ Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete remission for more than 2 years. Blood. 2007;109:58-60.

²⁴ Ault P, Kantarjian H, O’Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. Journal of Clinical Oncology. 2006;24:1204-1208.

²⁵ Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European Net. Blood. 2006;108:1809-1820.

²⁶ Kantarjian H, Shiffer C, Jones D, et al. Monitoring the response and course of chronic myeloid leukemia in the modern era or BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood. 2007; advanced on-line publication on November 30, 2007.

²⁷ Ross DM, Branford S, Moore S, et al. Chronic myeloid leukemia, BCR/ABL studies and myeloproliferative disorders. Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML-patients monitored by RQ-PCR for BCR-ABL. Leukemia. April 2006;20:664-670.