Transplantation and Cellular Therapy 28 (2022) 793794
`
`Transplantation and
`Cellular Therapy
`
`j o u r n a l h o m e p a g e : w w w . t c t j o u r n a l . o r g
`
`The Bottom Line
`Allogeneic Transplantation for Older Patients with Acute Myeloid
`Leukemia: The Dawn of a New Era
`
`Richard J. Lin, MD, PhD*
`
`David H. Koch Center for Cancer Care, Memorial Sloan Kettering Cancer Center
`
`Outcomes among older patients with acute myeloid leuke-
`mia (AML) remain dismal over the last few decades based on
`many registry-based studies, largely due to the general higher
`disease risk, co-existing medical comorbidities, compromised
`performance status, and the inability to deliver curative intent,
`allogeneic hematopoietic cell transplantation (alloHCT) to the
`majority of these patients [1]. AlloHCT is effective in curing
`selected older patients with AML who can achieve disease
`remission as compared to non-HCT therapies [24], yet chro-
`nologic age alone, “ageism”, has been consistently found to be
`the most common barrier for referring older patients with
`advanced hematologic malignancies for consideration of
`alloHCT [5].
`There is light at the end of the tunnel, however. In this issue
`of the journal, Mau L et al. used Medicare claims data to exam-
`ine trends and factors associated with alloHCT utilization
`among Medicare beneficiaries with AML and estimated unmet
`need for alloHCT in the modern era (2010-2016). They found
`that alloHCT utilization rate had increased gradually over time
`among Medicare beneficiaries with AML, culminating in 15.8%
`within 6 months and 20% within 1 year of AML diagnosis. The
`lower likelihood of receiving alloHCT within 1 year of AML
`diagnosis was associated with earlier year of diagnosis, older
`age, non-white race, certain geographic regions, higher comor-
`bidity burden, and lower household income. Moreover, using
`either the claims data approach or the NMDP (National Mar-
`row Donor Program) methodology, the authors estimated that
`there was 43-44% of unmet need among AML patients who
`could benefit from alloHCT, albeit with a downward trend
`over time.
`How do we account for these improvements, and can we
`expect the trend to continue? There are many reasons to be
`optimistic. First, we are in an era of unprecedented, rapidly
`expanding treatments for AML, many of them specifically tar-
`geting the older patient population. Since the approval of
`hypomethylating agents in the early 2000s as the low intensity
`AML treatment and after the study period described in this
`manuscript, we have witnessed a period of breakthrough drug
`approvals for AML including B-cell
`lymphoma 2 (Bcl-2)
`
`*Corresponding author. Tele: (646) 608 2646; Fax: (929) 321 8169.
`E-mail address: linr@mskcc.org
`
`inhibitor, venetoclax; two FMS like tyrosine kinase 3 (FLT-3)
`inhibitors, midostaurin and gilteritinib; two isocitrate dehy-
`drogenase (IDH) inhibitors, ivosidenib (IDH1 inhibitor) and
`enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug con-
`jugate, gemtuzumab ozogamicin; the oral hypomethylating
`agent azacytidine Onureg (as maintenance treatment); the lipo-
`somal formulation of cytarabine and daunorubicin, Vyxeos; and
`the hedgehog signaling pathway inhibitor, glasdegib [6]. While
`these new agents are not considered curative treatment, they
`are generally better tolerated than traditional intensive induc-
`tion therapies such as “7+3”, and generally more effective when
`combined than traditional low intensity, single hypomethylat-
`ing agent. Perceivably, these drugs could improve upon the
`meager 30-40% complete remission rate following initial treat-
`ment we see with older AML patients, and perhaps more prom-
`isingly, safer bridging therapy to curative alloHCT [7,8].
`In parallel to this improvement in AML therapeutics, we are
`also learning to select more appropriate older patients and
`take better care of them during the intensive treatment phase
`using geriatric assessment (GA)- based strategies [9]. GA is a
`multidimensional, multidisciplinary,
`comprehensive,
`and
`holistic assessment to evaluate an older person’s functional
`and cognitive ability, physical mobility, mental health, and
`socioenvironmental circumstances, and to design optimization
`strategies, both of which are now increasingly utilized for
`peri-transplant evaluation and management of older patients
`with hematologic malaignancies [10]. Several common geriat-
`ric deficits
`including functional
`impairment,
`cognitive
`impairment, and polypharmacy have been shown to be associ-
`ated with alloHCT outcomes including survival and treatment-
`related toxicities [11]. Moreover, a GA-guided, outpatient
`clinic-based, multidisciplinary pre-transplant optimization
`program for older patients has been shown to effectively
`reduce transplant-related mortality and improve survival in a
`pre- and post-study design [12]. Despite these advances, how-
`ever, many barriers exist to fully integrate GA into transplant
`practice including physician perception, time, staffing, and
`knowledge base [13].
`Finally, and perhaps most importantly, we are also seeing
`significant improvements in alloHCT outcomes in recent years
`[14,15], especially for older patients [16]. These improvements
`could be attributed to the development of reduced-intensity
`
`https://doi.org/10.1016/j.jtct.2022.11.002
`2666-6367/© 2019 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.
`
`CELGENE 2094
`APOTEX v. CELGENE
`IPR2023-00512
`
`

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`794
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`R.J. Lin? / Transplantation and Cellular Therapy 28 (2022) 793794
`
`and non-myeloablative conditioning regimens [17,18], advan-
`ces in supportive care such as newer anti-microbials, better
`prophylaxis and treatment of graft-versus-host disease, and
`more recently, increased donor choices across the HLA barrier
`[19]. Specifically for older patients, the recent development of
`treosulfan-based conditioning regimen with reduced toxicity
`and improved anti-leukemia activity, as well as potential anti-
`body-based conditioning strategies may further improve toler-
`ability of alloHCT for older patients [20,21]. Lastly, the role of
`maintenance therapy post-alloHCT may be of heightened
`importance in older patients, given the generally higher dis-
`ease risk and lower intensity of conditioning even with posi-
`tive measurable residual disease (MRD+) remission status
`prior to alloHCT [22,23].
`With these advances, we are seeing the dawn of a new era
`for older AML patients with improved ability to effectively
`bring them to the curative intent alloHCT and take them
`through the intensive alloHCT procedure. Despite these advan-
`ces, however, many barriers identified in this manuscript and
`others will continue to exist. We must leverage these AML
`treatment advances to educate clinicians, patients, and care-
`givers on selecting appropriate induction regimen, integrating
`GA across the treatment continuum, and making early alloHCT
`referrals to maximize their chance for cure. Clinicians, profes-
`sional societies, and policy makers should also have keen
`awareness to these social economical barriers and to develop
`systemic changes to address them to improve patient out-
`comes.
`
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