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How I Treat Series on the 25th anniversary of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
00:34:54
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- [00:02]
A
Welcome to this week's bonus episode of the Blood podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Jason Gottlieb discusses the How I Treat series in Chronic myeloid leukemia with Drs. Neal Shaw, Simona Silverini, Elizabeth Abruseze and Yves Schollendon. This How I Treat series and podcast commemorate the 25th anniversary of the introduction of tyrosine kinase inhibitors in CML, which has revolutionized the care of patients.
- [00:42]
B
Today we welcome Blood's audience to a special edition of its podcast series. My name is Jason Gottlieb and I'm an Associate Editor for Blood. Today's podcast is offered in conjunction with the Journal's How I Treat series in chronic Myeloid leukemia, which commemorates a quarter century since the introduction of tyrosine kinase inhibitors for the disease. While a generation's worth of trials has informed the evolution of management guidelines, this case based series reinforces the paradigm that an individual's care is still tailored to unique patient and disease related characteristics. Joining me on today's podcast are the authors of these How I Treat articles. They include Dr. Neal Shaw from the University of California, San Francisco who with Ariel Leyte Vidal discuss how they individualize treatment for chronic phase CML. Dr. Simona Severini joins us today from the University of Bologna with Fazdo Casagnetti. They have contributed a piece on how they evaluate and treat resistance in relapse in CML. Dr. Elisabetta Abruzzese joins us today from San Eugenio Hospital in Rome and with Ekaterina Kilischeva have authored the piece How I Manage Chronic Myelokemia during Pregnancy. Finally, Yves Chalandon is here today from the University of Geneva in Switzerland with Federico Simonetta and Stavroula Massoridi Levrat. They discuss their approach to hematopoietic stem cell transplantation for CML in the TKI world. Although not joining us for the podcast today, this How I Treat series also includes articles by Dr. Michael Morrow from Memorial Stone Kettering Cancer center, who addresses how he treats advanced phases of CML, and Dr. Nobuku Hajiya from Columbia University Medical center, who with Jing Chen and Minof Suttorp authored a piece on management of CML in children and adolescents. With this background, I'd like to extend a warm welcome to our podcast participants and use this opportunity to thank you all for your contributions to this series and today's podcast. Dr. Shot how about we kick off today's conversation with Hugh in your practice? What do you consider to be A FULSOME workup for the newly diagnosed CML patient to optimize decision making about treatment.
- [03:00]
C
To inform the initial choice of treatment, it's important to incorporate the patient treatment goals, comorbidities, disease phase and risk score. It is recommended to obtain a CBC with differential complete metabolic panel, quantitative pcr for bcr able1 and fish for bcr abl1 in the event that CML is suspected but the PCR test result is unexpectedly negative. Documentation of spleen size below the left costal margin on clinical exam, myeloid gene mutation panel, hepatitis B serologies, thyroid function tests should also be performed and the SoCal or ELTS risk score should be obtained. If the patient is potentially eligible for bone marrow transplantation, then bone marrow biopsy and aspiration to include flow cytometry and metaphase karyotype should be performed to confirm the disease phase.
- [04:03]
B
Thank you Neil. And you know, with 25 years of experience with TKIs and five agents approved for frontline use, can you discuss your thinking about how individualizing therapy has evolved based on based on patient and disease related factors?
- [04:19]
C
Yeah, we have abundant evidence that overall survival of chronic phase CML is excellent irrespective of which TKI is initiated. We do know that deep molecular responses are more common with second generation TKIs and asiminib, so treatment goals can impact the TKI choice. For people interested in eventual treatment, free remission or tfr TFR is particularly appealing for younger patients and those wishing to become pregnant. Patients with intermediate high SoCal risk or ELTS score fare better with second generation TGIS or asiminib compared with imatinib. There are also evolving data that patients with ASXL1 mutations may preferentially benefit from these newer agents rather than imatinib in terms of depth and durability of response. Certainly comorbidities can impact the choice of therapy as well as treatment schedule. For instance, the range of dosing schedules varies from once daily with or without food to twice daily fasting and everything in between. We've learned that variants that lack ABL1, Exon2 are inherently resistant to asiminib, so determining the transcript type can be of importance. Another factor gaining increasing attention is the cost of TKI therapy. Not only cost to the patient, but also to society. For instance, four of the five approved frontline TKIs are now available as generics in the USA and in some cases their annual societal cost is greater than 100 fold lower than brand name alternatives.
- [05:59]
B
Thank you Neil. And someone let me pivot to you for the patient diagnosed with chronic VASE cml. Can you comment on the scope of the problem of resistance in patients on first and second generation TKIs? And additionally, can you just discuss how the ELN and NCCN guidelines are used by physicians to help guide monitoring of therapeutic effect?
- [06:20]
D
Yes, TKIs are very effective drugs, yet we have to face resistance in some of our CML patients frequently. While it can be estimated that treatment switch for an unsatisfactory therapeutic effect occurs in up to 20 25% of patients receiving first line imatinib and in 10 to 15% of patients treated with second generation TKIs. And how can resistance be defined? Both the ELN recommendations and the NCCN guidelines provide us with important guidance in this regard. So bearing in mind that the gold standard for the evaluation of therapeutic efficacy is molecular response as assessed by real time quantitative RT PCR for residual B cerebral transcripts. The stepwise achievement of key molecular response milestones, which means key reductions in PCR reboot transcript levels at given checkpoints during therapy, is used to define a satisfactory response trajectory. So the lack or the loss of these milestones define what is resistance then? There are slight differences in timings, levels and terminology between the ELN and the nccn, so for example the ELN is bit more demanding. The most recent ELR recommendations have mitigated the term failure into unfavorable and now distinguish between unfavorable, which means higher risk of resistance and warning possible resistance. Whereas the NCCN uses a traffic light color code for resistance or possible resistance anyway, both provide a good toolbox to identify or to anticipate resistance in our patients.
- [08:22]
B
Can you elaborate on what are the disease intrinsic and extrinsic causes of an unsatisfactory therapeutic response and what causes should we think about and test for?
- [08:34]
D
Yes, the most frequent extrinsic cause that we should carefully investigate directly with our patients is nonadherence. Then we should also think about drug interactions reducing TKI bioavailability, especially in elderly patients who are likely to take many concomitant medications. So these two factors should always be ruled out first. Also, the occurrence of hematologic or non hematologic toxicities requiring temporary treatment discontinuation or those requirements reductions may have a role in slowing down the molecular response trajectory or precluding the achievement of an optimal response, and this must be borne in mind as well. Then the disease intrinsic causes include several bcrable dependent or independent biological factors, not necessarily mutually exclusive, but the only ones that can routinely be investigated and provide clinically meaningful information are the acquisition of additional cytogenetic abnormalities and the acquisition of point mutations in BCRL1. This may either impair drug binding affinity or interfere with the mechanism of action of one or more TKIs, so BCR abled mutation testing should always be performed whenever considering a change of TKI due to resistance, since mutation status may impact on second or subsequent line TKI selection. And both the ELN and the NCCN provide up to date tables for the interpretation of mutation status only for asiminib, but this information is still provisional thank.
- [10:30]
B
You Samana and Elizabeth Let me ask you about pregnancy and can you discuss the three considerations for women contemplating pregnancy which you divide into CML related factors, pregnancy related factors, and patient related factors?
- [10:45]
E
Certainly, that's a great question and really the cornerstone of our article. When a woman with CML is thinking about pregnancy, there are different areas to consider and each one brings to its own challenges. First, the CMS related factors where we look at the biology of the disease, the phase of cml, how well it's controlled, and what kind of therapy the patient is receiving. A woman in chronic phase with a deep and stable molecular response is in a completely different situation from someone newly diagnosed or with less stable disease. The type of TKI used and the timing of exposure are also key because they determine both maternal safety and physical fertile risk. Then come the pregnancy related factors which are more about timing and circumstances. Is the pregnancy planned or unplanned? At what stage of gestation is the diagnosis made and how long has the fetus been exposed to treatment? These are crucial details because management decisions change completely depending on whether CML is discovered during pregnancy or whether a woman already on treatment becomes pregnant. Finally, the patient related factors and maybe the most delicate age parity, overall health, emotional, cultural and social background. All of these influence not just medical choices, but also how a woman and their family experience those choices. So the challenge lies in balancing all those dimensions at once. There isn't a single right path or a right answer. It's a highly invidious, individualized process that require close collaboration between patient, family and physicians. This complexity is explored through real cases showing how nuanced and hopeful this journey can be when decisions are shared and well guided.
- [12:38]
B
In your article you discussed CML diagnosed during pregnancy versus pregnancy during CML treatment. For patients with CML diagnosed during pregnancy, can you comment on general treatment considerations based on disease status and trimester?
- [12:53]
E
Sure, that's an important distinction. When CML is diagnosed during pregnancy, the approach really depends on two the disease status and the timing within pregnancy. If the diagnosis happens in the first trimester, this is the most delicate period because organ development is underway and most anti leukemic drugs, especially TKIs, are contraindicated due to their potential teratogenic effects. Effects in these cases, if the disease is stable and there's no severe leukocytosis, we can sometimes simply monitor closely without starting therapy. But if there's an urgent need for cytoreduction, for example more than 100,000 white blood cells or more than 1 million platelets, we rely on safer options like interferon alpha that can be used throughout the pregnancy. In the second and third trimester, once the placenta is fully formed and organogenesis is complete, the therapeutic window widens a little for women who require more active disease control. Certain TKIs, particularly imatinib or nilotinib that poorly cross the placenta can be considered after 16 weeks, always weighing maternal benefit against fatal risk. For the other TKIs, Dasatinib should not be used at any time during pregnancy and we have no information concerning the crossing of the placenta for the other newer drugs.
- [14:24]
B
Thank you. Elizabeth and Eve. Let's pivot to the issue of transplant. Clearly the frequency or use of transplant is less in this so called TKI world. But can you comment on the most common indications for transplant in 2025?
- [14:41]
F
Yes, thank you very much. Yes, you're right, it has decreased, but there are still some indication even though. And the most common indication for transplants nowadays are advanced phased cml. For instance, in the European registry of the European Society of Blood and marrow transplant, the EBMT, between 60 and 70% of the patient transplant were in advanced phase, either an accelerated phase last phase or cml, which were more than first chronic phase, which is not so good because the result of transplant in advanced phase CML are much worse than in first chronic phase. Therefore, it's of utmost importance to bring the transplant patient who are still in first chronic phase and not in advanced phase unless they present themselves at diagnosis in advanced phase. Patients who have failed at least two or three lines of TKI in clinic Ponatinib and nowadays, if available, for instance asiminib, are the most common chronic phase CML patients transplanted.
- [15:54]
B
Thank you. And can you discuss the issue about timing of transplant risk? That is, sometimes we may wait too long or proceed too early. What are the major patient and CMO related factors in your evaluation of risk and how those impact the urgency regarding moving to transplant?
- [16:11]
F
Thank you for that question, which is an important one. The timing is truly important and not always very well considered and physician must be aware about that issue. As mentioned previously, the most important factor is the stage of disease, meaning that transplant should be done in first chronic phase if possible and not let the patient proceed to advanced phase. Therefore, it's important to monitor closely the CML patient and in case of molecular progression with a clear ascending kinetic of the molecular marker to be ready to change tki. When patients are young and have received third generation TKI and progress on this therapy, they should be addressed transplant rapidly before the disease progress to accelerated or blast phase. The same holds true for patients who are intolerant to all tki, particularly the one with hematotoxicity with whom you cannot maintain a good pressure on the disease because of many interruption of TKI therapy and the risk to have TKI resistant mutation. Also, there is no very good predictive score, but at least from the moment the high LTS score in a young patient will ask to discuss transplant indication.
- [17:35]
B
Thank you very much Eve and Neal. I'd like to return to you and talk about the nexus of patient age and TKI tolerance and patient's treatment goals. Some patients may earring for treatment for remission, others may be unsettled by the idea of discontinuing therapy. Can you discuss how you balance the dosing of TKIs e.g. dasatinib based on molecular milestones as well as patient age and goals?
- [18:01]
C
The first thing I want to say is with respect to treatment free remission attempts. This should always be driven by the patient if they meet the eligibility criteria. It's not something that we make recommendations on, usually for a patient, but for second generation TKIs and asiminib it has become clear that lower doses of these agents can be effective and well tolerated with dasatinib. For example, a single arm study from the MD Anderson Cancer center demonstrated comparable response rates with 50 mg to historical experience with 100 mg and what appears to be better tolerability with a lower dose. I generally initiate a dose of 50mg dasatinib in individuals who are 60 years and older. They are at higher risk of pleural effusion and I think this can mitigate that risk substantially. I also commonly dose reduce dasatinib and other TKIs in responding patients who are meeting treatment milestones but are perhaps having some side effect issues that are unpleasant with dasatinib. If they start 100 milligrams and they're meeting milestones but having some potential toxicity issues, I will go to 50 or even 20 milligrams in many cases. Of course, it is important to continue to monitor response carefully. There are insufficient data to know if the likelihood of achieving a deep molecular response is possibly lower with lower doses. So a discussion of how to manage expectations of response with tolerability is important.
- [19:41]
B
Thank you. Neil and Simona, acknowledging that treatment choice for cases of resistance are undertaken on a case by case basis, can you discuss the major variables that influence decision making in everyday practice?
- [19:55]
D
True Jason, individualization is the key. Even more here so one for all rules cannot be formulated since for each patient the decision process requires investigation and integration of a series of disease and patient specific factors. So in detail. First, the treatment history, that is the type and the dose of the TKI or tkis previously used because there are some general rules helping to avoid inappropriate treatment sequencing. For example, in case of resistance to a second generation TKI that was taken at the full dose, Ponatinib or Assiminib should be preferred over another second generation tki. Second, the disease biology, the bcerebral transcript levels as a mirror of the severity of resistance and the presence and type of bcerebral mutations. Bearing in mind that mutation status may be a surrogate marker of genetic instability and disease propensity to escape and should be used to exclude one or more TKIs from the algorithm rather than to select among the remaining ones the TKIs that is likely to be more effective. So please refrain from using the IC50 tables. Third, patient features the same more or less that have already been mentioned by Neil, so age, comorbidities, the risk as already mentioned, but also the specific treatment goals we have agreed with this patient.
- [21:40]
B
Thank you Simone and Elizabeth. For patients who become pregnant with an established diagnosis of cml, can you touch on the basic factors that influence when to stop treatment, when to restart or initiate therapy, and how do you approach post delivery care including breastfeeding and perhaps even comment on how treatment for remission impacts decision making in this setting?
- [22:01]
E
Yes, very important points. Let's start with the last question first, since that is really the best case scenario. A woman who has been in a stable TFR for more than a year, knowing that most of the relapses occur within the first three to six months, is in the ideal position to proceed with pregnancy monitoring can safely follow the standard three months schedule and so far there's no evidence that pregnancy itself triggers molecular relapse. So these women can be reassured and encouraged while continuing their molecular follow up. But not all the pregnancies are planned nor all the Patients are in deep molecular response or able to be in tfr. So for women still still on therapy, decisions become more complex and hinge on three key when to stop, when to restart, how to manage postpartum care. Stopping TKI as soon as pregnancy is confirmed, ideally at the first positive pregnancy test between the third and the fifth week of pregnancy, helps avoid fatal exposure during organogenesis, but it requires awareness in monitoring the menstrual cycle. If transcript levels after stopping remain stable we can simply monitor, but if they rise rapidly or if the disease burden is high, we may need to introduce treatment most often as said interferon alpha or imatinib and or nilotinib. After delivery, the focus shift to when to resume therapy and whether breastfeeding is possible. And here some common sense should come and also thinking about how the pregnancy has gone throughout the time women in a TFR or on interferon can safely breastfeed, while if the mother restarts a TKI even through drug concentration in breast milk are very minimal. Breastfeeding is generally discouraged. But but if a patient is on Mr. 2 and on interferon or still in TFR, we usually just closely monitor and see if the transcript is going up before restarting therapy allowing her to breastfeed.
- [24:22]
B
Thank you very much Lizbeth and Eve, Let me come back to you and let's talk briefly about post transplant and how you employ TKIs either preemptively or only with having some electrical relapse. And perhaps you can also comment on the role of DLI in 2025.
- [24:40]
F
This is important as the role of DLI was very important prior to the TKI era and this has evolved frankly. But first TKI post transplant it depends on the stage of disease at transplant. For instance, patients who were transplant in advanced pace will most probably receive TKI in the post transplant maintenance after engrafting starting about two months post transplant when a sustained engraftment has been insured for chronic phase CML patients, this will be guided by the kinetic of post transplant molecular evaluation which is regular post transplant at least every three months. If there is molecular relapse that is confirmed, then a treatment will be initiated. Concerning the use of dli, this depends also on the transplant setting and if the disease is resistant or not to tkis at transplant, for instance, you may manipulate the graft for T cell depletion either in vivo or in vitro to decrease the risk of gbhd, but there is a huge risk of molecular relapse or progression and then you will use first tki then to decrease the molecular relapse. And at least after six months post transplant when the risk of TBHT is lower and CML is still very sensitive to immune therapy, then you can increase the dosage DLI every eight weeks to control the disease. This is also true for patients that are multi resistant to tki. Then you have only DLI to work on and this is one of the reasons to use this kind of therapy. Then you can also use it sequentially, first TKI then DLI, first TKI to maintain bcr abl below 3 lock and then to have time to get give DLI at a time point when the disease risk of TVHD is much lower. So it depends on the transplant strategy if DLI may play more or less.
- [26:55]
B
An important role thank you Eve and perhaps we can wind down the podcast by a lightning round and I'd like to ask all of you in a forward looking way, what do you think are the unmet needs or exciting areas of research in each of your domains of expertise in cml? And perhaps Neil, I can start with you.
- [27:17]
C
I think that there are ongoing studies to see if disease response and progression can be actually predicted at the time of diagnosis. This could help identify patients early who may benefit from allogeneic stem cell transplantation prior to the development of accelerated or blast phase disease. There is still substantial room to improve deep molecular response rates in chronic phase CML patients in an effort to make TFR a possibility in a higher proportion of these patients. There are ongoing studies of novel strategies to deepen molecular responses with TKIs, typically with the use of adjunctive agents, although this is a challenging area for drug development because any novel adjunct of the therapy needs to be very safe and well tolerated. Just given the excellent prognosis of chronic phase CML patients with the available therapies. We also we do need a better understanding of how to improve outcomes in patients who have coexisting ASXL1 mutations. And lastly, I would say for patients in whom lifelong treatment appears to be likely, reduced doses of TKIs can be beneficial to mitigate chronic low grade toxicities and improve quality of life.
- [28:37]
B
Thank you Neil and Simona, can you talk to what excites you about future and research opportunities?
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D
Well on the clinical side we certainly need more weapons also for resistant patients. So new tki, new concepts of targeting BCR ABL like complete elimination by degraders, new combos, more or less the similar issues that have already been mentioned by Neil. And on the lab side the very first unmet need we should address is to fill the gaps in the puzzle of bcrable mutations conferring resistance to asiminib and other STAMP inhibitors and to assess assess whether we should extend the borders of our mutation testing assays beyond the kinase domain. Then I can think about exploring the role of wider genomic characterization of resistant patients through NGS panel sequencing or even whole exome sequencing or whole genome sequencing. Once more widely, logistically and and economically accessible to see whether given genomic profiles may fit into our decision algorithms or to highlight draggable alterations and therapeutic targets additional to bcrable ones. Again to counteract resistance in our patients.
- [30:04]
B
Thank you Simone and Elizabeth, can you comment on that areas that need for the research in the setting of TKIs in pregnancy?
- [30:13]
E
I like to think that thanks to the whole scientific community we made tremendous progress. Just a decade ago pregnancy in CML was a taboo topic. Now it's allowed and the growing body of data has helped guide the clinical decisions. Still, there's always more to learn. As we heard from Dr. Neal Shah, there are newer drugs and the studies on their safety and the optimal timing of their use is expected. And shall I promote our posterior dash that will present to 44 pregnancy cases with asiminib? Well, I did. Fertility preservation is another important point. And assistant reproductive techniques also need attention, particularly for patients with advanced disease or those who are transplant candidate that are still there, as we heard from Dr. Charlendon. And we also need to understand the long term outcomes of children exposed in utero to TKIs or interferon, not just at birth, but in terms of growth, narrow development and future fertility. And finally there's the human side. Expanding knowledge among hematologists, improving communication with patients and developing individualized multidisciplinary care pathways are crucial because as seen in the manuscript, real life cases often challenge even the best guidelines. So science is strong, but the story is still evolving. And the goal now is to make pregnancy in CML not just possible, but predictable and safe for everyone and everywhere, because there's not only our countries to be considered.
- [31:51]
B
Thank you Elizabeth. And finally Eve, can you discuss what are some rich areas of research for transplantation?
- [32:00]
F
Transplantation is much rarer for CML Nowadays it's about 2 to 3% of the patient who will need transplants. So research has been weaker in that field. And for the moment what is important I think is try to improve the capability of decreasing toxicity and also mortality related to the transplant setting, which was very problematic 20 years ago. Nowadays we have improved our support supportive care so it clearly go below 10 or even 5% of transplant related mortality if you have a HLA identical sibling and if you can manipulate the transplant product for instance. That's what we are doing in our centers and we have huge experience with 20 years follow up of those patients and those patients they are alive with 88% of the patient and free of GVHD, free of any TKI and cleaning quite well. So the importance is to do such a manipulation so you avoid to have too much lymphocyte load during transplant with the conditioning and the cytokines form and the infection and also the hematologic frailty and you differ and the abbag of the lymphocyte at 6 or even more a month post transplant. The risk of molecular progression is important so you may have to play with CKI meanwhile and try to improve that issue. The imbalance is not easy to find between manipulation of cells, but cement, as I mentioned before, is one of the most immunological sensitive disease. So that's where we need to improve our research project to decrease the risk of transplant toxicity and play with the lymphocytes to help control the disease in the long term.
- [34:12]
B
Thank you very much Evan. With that, I'd like to conclude today's wonderful discussion by acknowledging Neil and Simona and Elizabeth and Eve for their work on the series and podcast and for the contributions to the CML field. We hope that Blood's readership finds the How I Treat articles a valuable educational resource for managing their patients.
- [34:41]
A
Thank you for listening to this bonus episode of the Blood Podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.