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• W2952555327 abstract "Much has been written and discussed related to the recent plethora of drug approvals by the United States Food and Drug Administration (FDA) for acute myeloid leukemia (AML).1-4 This topic has been met with appropriate enthusiasm for the following reasons: (a) AML is among the most difficult cancers to treat, with very poor historical outcomes5; (b) Efforts to develop therapies for AML have been heroic, with more clinical trial activity for this disease than many more common malignancies6; and (c) Until recently, these efforts were largely unsuccessful.7 It is now appropriate to reflect on the present and future landscape for drug development in AML, and to contrast it with the earlier fallow period, in order to determine what lessons may be learned and obstacles avoided. It is my belief that the development and FDA approval of venetoclax represents a paradigm shift in how AML is and will be treated, and this editorial is built on the premise that venetoclax is practice-changing in AML.8, 9 Those who disagree with this conclusion will find fault with many observations and suggestions herein. Despite this, it is my position that we are in a new “post-venetoclax” era, which necessitates the following changes in drug development strategies to ensure continued successes. The success that has led to the recent drug approvals in AML has many fathers; improved understanding of the biology of AML, industry drug pipelines with more and better therapies, and more efficient accrual to better designed clinical trials are all factors that deserve credit for the embarrassment of riches that we now enjoy. However, what cannot be overlooked is a more liberal policy in the way the FDA evaluates the beneficial nature of a drug for AML. While an overall survival (OS) benefit for a new therapy in the setting of a randomized study compared to an accepted standard of care was previously the necessary metric for approval,10 four of the eight drugs approved or reapproved since 2017 did not clear that bar (enasidenib, ivosidenib, gemtuzumab ozogamicin, and venetoclax). This more liberal stance by the FDA has not necessarily been adopted by the regulatory bodies of other regions and countries, and considerable debate over which endpoints are the most relevant on which to base approval exists.11-14 Treating patients in the clinic, I find it challenging to argue that limiting the weapons in our arsenal would be desirable, and in fact find considerable flaws in the higher standard-for-drug-approval approach. Primarily, in the relapsed setting, clinical scenarios are variable. Some patients cannot tolerate more intensive chemotherapy, others can; some patients have relapsed after many therapies, others after relatively few. Even if the expected strategy were to be to design multiple independent clinical trials to address each possible scenario (which would be impossibly limited by the disease incidence and patient accrual to studies), the field does not have an accepted standard of care for these various clinical situations, making insistence on improved OS from a randomized study an unreasonable expectation. In the up-front setting for older patients unfit to receive induction chemotherapy, the landscape was until recently bizarre, due to the fact that the de-facto standard of care, a hypomethylating agent, is not an approved therapy for this situation and was widely given because of the results of a randomized study showing a marginal survival benefit compared with doing nothing or administering intensive chemotherapy (azacitidine15) or did not result in an OS benefit (decitabine16). It is unreasonable to stall drug development because a new therapy cannot be proven superior to a standard of care when experts are unable to define what the standard of care is. We should instead acknowledge this difficulty, and make aggressive attempts to recognize when relatively large, multi-institutional single-arm studies report responses that seem unusually positive. Perhaps we should attempt to define this “super response rate,” which, if reached, could trigger FDA approval for more widespread use. The idea would be to attempt to define objectively the “Your Mother Test”: Despite high-minded thoughts about conservative drug development strategies that require years of testing to show an OS benefit, would you direct your mother, should she get AML (and assuming you love your mother) to receive a particular promising therapy? If so, super-rational leukemologist colleagues, it should probably be approved for everybody's mother. In 1973, we got into a bad marriage. Our betrothed was the sexy new 7+3 regimen.17 We were willing to overlook that he could be prohibitively toxic, that he was not effective for the majority of patients, and we certainly did not seem to mind back then that we were marrying a treatment that was never shown to be superior to a standard of care.17 The truth is, we did not have a lot of suitors and we really wanted to get married. Over the years, we have tried changing her,18, 19 adorning her,20, 21 and have traveled the world with her pretending she is different there.22-25 After over 45 years together, despite sometimes saying awful things about her in public26, 27 and increasingly realizing that he can make the disease he is supposed to treat worse,28-31 we have become unhealthily codependent. As any therapist or good friend would advise, we must stop perpetuating this union. We need to divorce ourselves from 7+3. When early phase studies produce a promising new agent, which typically first occurs in the relapsed or unfit setting, the instinct is to add it to induction chemotherapy for younger, fit patients. This strategy has many shortcomings. First, the response rate for induction is already relatively high; our difficulty in treating AML is usually not related to our inability to get patients into remission, it is our inability to prevent them from dying from relapse. Therefore, it is very likely that in a large, randomized study, the addition of a novel therapy will not result in a discernible benefit with respect to response (midostaurin serves as an excellent example of this concept32). With a large enough study and long enough follow up, one could hope that an OS benefit could be observed. However, the nuances of transplantation and the variety of treatments given in the relapsed setting could mask this observation, even if it were not limited by very long follow up times and changing standards of care in the interim. In addition, as stated above, this strategy forces us to perpetuate a regimen that has never itself proven to be superior to a standard of care.17 What does it mean to be “fit” for 7+3? There is extensive historical baggage that must be unpacked when considering this question. For decades there were no other treatment options besides 7+3, so ascertaining a patients' “fitness” for this therapy was hugely consequential; it was a surrogate for asking whether or not a patient should receive treatment at all. A “fit” patient had a treatment option; an “unfit” patient faced certain death. As a result there was understandable debate on the topic of the appropriate objective or subjective definition for fitness.33 This question cannot be settled; there will never be a universally accepted way to define “fitness.” It is therefore fortunate that the question is no longer relevant. With a 70% response rate and a remission duration that had not yet been reached after a median follow up time of 15 months with venetoclax 400 mg and azacitidine, a comparatively well-tolerated toxicity profile and an early death rate of 3% for venetoclax at all doses with either hypomethylator,8 the question of who is “fit” for 7+3 takes on a considerably different significance. With treatment-related mortality rates that can approach 20% and an inability to cure the disease outside of the favorable risk subtypes,34, 35 why should one need prove her worthiness for 7+3? I propose we start with the premise that nobody is fit for this brutal and toxic regimen. Once that is established, it would be reasonable to ask who might be expected to derive benefit from this approach over a less toxic and highly effective alternative: certainly favorable risk patients; not those with adverse risk disease biology or those 60 years and older.34, 36 If we agree that induction chemotherapy is, a) an anachronism, grandfathered in as the standard of care under less rigorous standards than we hold current therapies to, b)helps only a sliver of our patients and worsens the disease in the majority who relapse, and c) resulted in static advances in our field for decades, we should unhitch our wagons and not look back. Combination studies involving promising new therapies should be guided by science and not convention. We live in an era in which databases of hundreds and sometimes thousands of patient samples have been interrogated and await our hypothesis-testing37, 38; the BEAT AML data set contains detailed information on primary samples' sensitivities to 122 therapies.39 We have access to synthetic lethal screens and sophisticated animal models. For decades, by necessity due to the lack of these tools, combination studies were conducted based on theories about how drugs “should” synergize, or by tacking promising agents onto accepted backbone therapies (see above section regarding 7+3). I believe it is no coincidence that this strategy overlapped with the fallow period for drug approval and advancement in our field. Moving forward we should pursue combination studies in patients only when they are supported by evidence of preclinical synergy. Resist the urge to propagate 7+3 or hypomethylating agents; if these conventional therapies still have a role to play in combination with novel therapies, they will have to earn their continued relevance. The current guidelines recommend bone marrow biopsies to assess responses after 28 days of initial therapy.40, 41 This is of course based on widespread experience with induction chemotherapy; in that setting, patients are treatment-free for 3 weeks at the time of this assessment. Assuming patients had achieved a morphologic remission at this time-point, the recovery of peripheral blood counts was an important prognostic factor; patients who achieved a complete remission (CR) with incomplete recovery of peripheral blood counts (CRi) did not live as long as patients who had achieved a CR with full blood count recovery.42 In clinical trials in which patients receive low-intensity (but still to some degree myelosuppressive) regimens, they continue to be assessed for response after 28 days of treatment, with no break from therapy at the time of the bone marrow examination. There is an assumption that under these conditions, incomplete blood count recovery remains a poor prognostic factor on a day 28 bone marrow biopsy. This is an assumption that requires further investigation. Regardless, I suggest it is appropriate to document a morphologic remission on day 28 and if present, to hold therapy for a brief period, perhaps up to 14 days. For patients without residual evidence of disease, I advocate giving growth factor support when neutropenia persists. Assuming no disease-modifying therapy is given in the interim, it would be appropriate to “upgrade” the response seen on day 28, from a morphologic leukemia free state to a CRi or CR or a CRi to a CR, if count recovery permits this during the 14-day period. Reporting this “upgraded” response will be a truer reflection of the actual activity of the therapy, and the pause with count recovery may be protective against cumulative cytopenia-related adverse events that might otherwise occur from plunging immediately into another treatment cycle. An advantage of being an AML clinician is that we have such a sophisticated understanding of the biology of this disease, largely due to the cytogenetic and molecular interrogation of such a large number of patients, allowing for real confidence when it comes to prognostication. However, the prognostic significance of cytogenetic and molecular abnormalities is almost all in the context of intensive induction chemotherapy. We extrapolate these assumptions to novel therapies at our own peril. We had reason to believe that leukemia stem cell (LSC) targeting therapies might not be impacted by traditional adverse risk disease factors,43, 44 and have shown that venetoclax with azacitidine targets the LSC population in a novel way.45, 46 Indeed, the presence of long-feared risk factors like complex karyotypes and mutations in FLT3 or TP53 do not appear to have a major impact on a patient's ability to respond to venetoclax-based regimens.8 There is precedence for this in other fields; the del(17p) abnormality in chronic lymphocytic leukemia used to be the major determinant of a bad outcome when chemotherapy was the only option; in the era of highly effective, targeted small molecule inhibitors, responses are largely agnostic to del(17p) status,47, 48 which has leveled the playing field with respect to this once-feared abnormality. This presents opportunities as well as challenges. AML patients with biological profiles that once made us shudder can have some optimism about their ability to respond to treatments in the modern era. Everyone in the community must become aware of this observation so that nihilism about treatment from outdated assumptions does not prevent patients from receiving effective therapies. Going forward, new therapies will almost certainly have new associated prognostic features, and determining these will give us insight into the mechanisms of resistance. A significant minority of patients are and will continue to be refractory to venetoclax-based regimens. We must work to understand who these patients are likely to be, comprehend the reasons for their suboptimal responses, and rapidly design clinical trials to exploit other relevant targets. Similarly, it is likely we will increasingly be dealing with the disease entity “AML, relapsed after venetoclax”; these patients may have disease resistance emerge in ways that would present therapeutic opportunities which are not currently considerations. This is a golden age for clinicians who treat AML. None of us, however, are content. Being thoughtful about the strategies we adopt now will allow us to continue the momentum, and I believe the critical first step on this path is to recognize we have entered a new era. This recognition will allow us to preserve the hard-won accomplishments of previous decades of work, but also to break with convention when necessary. This balance will require qualities that are abundant in our community: courage, vision, leadership, and brilliance. And if anyone knows a good divorce lawyer, that would help too." @default.
• W2952555327 created "2019-06-27" @default.
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• W2952555327 date "2019-06-25" @default.
• W2952555327 modified "2023-10-16" @default.
• W2952555327 title "Acute myeloid leukemia drug development in the post‐venetoclax era" @default.
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