Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation

Journal Pre-proof Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation

Bindu Kanapuru, Harpreet Singh, Virginia Kwitkowski, Gideon Blumenthal, Ann T. Farrell, Richard Pazdur PII:

S0268-960X(20)30020-5

DOI:

https://doi.org/10.1016/j.blre.2020.100670

Reference:

YBLRE 100670

To appear in:

Blood Reviews

Please cite this article as: B. Kanapuru, H. Singh, V. Kwitkowski, et al., Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation, Blood Reviews(2020), https://doi.org/10.1016/ j.blre.2020.100670

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2020 Published by Elsevier.

Journal Pre-proof Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation Bindu Kanapuru* [email protected], Harpreet Singh [email protected], Virginia Kwitkowski [email protected], Gideon Blumenthal [email protected], Ann T. Farrell [email protected], Richard Pazdur [email protected] Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA Abstract Despite a high incidence of hematologic malignancies in older adults, available data indicate

of

that there is disproportionately low representation of adults ≥65 years with hematologic

ro

malignancies (greater in patients ≥75 years) in clinical trials. Biological and clinical differences

-p

between older and younger adults and diversity within older patients necessitate adequate

re

representation of the older subpopulation in hematologic malignancy trials. This would allow trial results to be generalizable and inform treatment decisions in the older patient population.

lP

Restrictive eligibility criteria may be barriers to adequate representation, as older adults do not

na

typically meet these criteria. Efforts to broaden eligibility criteria in clinical trials have been proposed and may promote enrollment of a representative older population with hematologic

ur

malignancies. Collaboration amongst a diverse group of stakeholders will be needed to

Jo

implement current proposals and evaluate their impact on increasing representation of older adults in trials evaluating therapies for hematologic malignancies.

Keywords: Clinical trials, Older Adults, Hematological malignancies, Underrepresentation, Enrollment barrie rs.

Introduction Hematologic malignancies are most commonly diagnosed in adults 65 years and older and a significant proportion of these diagnoses are in patients 75 years and older [1]. The incidence of hematologic malignancies is expected to increase in older adults (≥65 years) due to the aging of

Journal Pre-proof the world population [2] and at a much higher rate than in younger adults. For instance, the incidence of multiple myeloma (MM) is expected to increase by 77% by 2030 in those over 65 years of age compared to a 57% increase in those 65 years and younger. The incidence of nonHodgkin’s lymphoma and leukemia is expected to increase by greater that 65% in those 65 years and older compared to less than a 50% increase in the less than 65 years age group (1). Although survival rates have improved for adults ≥65 years over the years [4], adults 75 years of

of

age and older with hematological malignancies continue to have the highest mortality rates among all age groups [5, 6]. Age is an important prognostic variable for survival, but evidence

ro

indicates that survival differences cannot be explained by chronological age alone. Underlying

-p

differences in clinical and patient related factors like disease biology [7], comorbidities [8, 9],

re

performance status in older and younger patients with hematologic malignancies as well as

contribute to poor outcomes [11].

lP

diversity within the older adult patient population with respect to functional status [10] may

na

Adequate and well-controlled clinical trials serve as the cornerstone for evaluating safety and effectiveness and are the basis for drug approvals by regulatory agencies in all patients,

ur

including older adults with cancer. However, less than 5% of adult patients with cancer are

Jo

enrolled in clinical trials [12] with lower rates in adults over 65 years with cancer. Previous publications that reported underrepresentation of older adults in cancer clinical trials have included only small numbers of patients on of hematologic malignancy trials and few reported enrollment rates for patients 75 years and older. Given the expected aging of the population and increasing incidence of hematologic malignancies in older adults, adequate representation of older adults in hematologic malignancy clinical trials is essential to understand the treatment effects in this sensitive subpopulation and make clinical trial results generalizable to them. Participation of older adults in clinical trials allows comprehensive evaluation of the risks and benefits of cancer drugs in older adults prior to approval and permit generalizability of clinical trial results to the patient population with hematologic malignancies. Underrepresentation of the

Journal Pre-proof older patient population may result in inadequate treatment or treatment with inappropriate doses due to lack of rigorous evidence from clinical trials and result in poor outcomes. The purpose of this review is to highlight the under-representation of older adults with hematologic malignancies in clinical trials relative to the proportion of older adults diagnosed with the disease. We focused on publications reporting rates of enrollment of older adults in hematologic malignancies from analyses of large clinical trial databases. Barriers to clinical trial

of

enrollment and current strategies particularly actions taken by the U.S. Food and Drug Administration (FDA) to address the current clinical trial landscape in this specific subgroup of

-p

ro

patients will also be discussed.

re

1.0 Burden of hematologic malignancies in older adult population

lP

1.1 Incidence of hematologic malignancies in older adults

na

Hematologic malignancies broadly classified as leukemias including acute and chronic leukemias and lymphomas including non-Hodgkin lymphoma (NHL) and Hodgkin lymphomas

ur

(HL) are a heterogeneous group of tumors arising from lymphoid system and bone marrow.

Jo

Data from population databases indicate that older adults shoulder a disproportionate burden of most hematologic malignancies. The median age at diagnosis reported in the U.S Surveillance Epidemiology Evaluation and Research (SEER) database for lymphomas is 65 years and 66 years for leukemias [1]. In the U.K Hematology Malignancy Research Network, median age at diagnosis was 70.0 years for total lymphoid malignancies and 72.0 for total myeloid malignancies [13]. Incidence rates based on recent World Health Organization (WHO) classification for these malignancies also suggest that majority of myeloid and lymphoid subtypes are also diagnosed for the first time in adults ≥65 years [13, 14]. The incidence of most hematologic malignancies increases with age (Figure 1a,1b) up to 85 years of age. The highest incidence rates reported in SEER for AML, NHL, multiple myeloma

Journal Pre-proof (MM) and chronic myeloid leukemia (CML) are reported in patients in the ≥80 years age group. The incidence of chronic lymphocytic leukemia (CLL) is highest in adults ≥85 years [1]. Adults ≥75 years make up nearly 30% of the population with an incident diagnosis of hematologic malignancy (Figure 2). Thirty percent of incident cases of CLL are diagnosed in the 65-74 years age group, 25% in the 75-84 years age group and 13% of the cases are diagnosed for the first time in patients 85 years and older.

of

HL is generally considered an uncommon cancer in the older adults with a median age in population registries reported to be between 39-40 years of age. However, patients with HL

ro

have a bimodal pattern of incidence with two peaks, in the 20-24 years age group and the other

-p

between 70-79 years of age. Approximately 18% of the newly diagnosed cases of HL are

re

diagnosed in adults 65 years and older with 9% of the incident cases diagnosed in the 65-74 years old age groups, and nearly 7% in those 75 years and older. Classical Hodgkin lymphoma

lP

(CHL) is diagnosed most often in the older age subgroups (70 years and older) [15]. Increasing

na

incidence of hematologic malignancies with age and higher incidence rates in adult 65 years and older have also been reported from other European registries [16, 17, 18, 19]. In the

ur

HAEMACARE project, a European Cancer registry-based project that collected the incidence of

Jo

HMs in Europe during the period 2000–2002 reported highest rates at 75-99 years age.

1.2 Older adults with hematologic malignancies continue to have poor outcomes

Adults ≥65 years particularly those ≥75 years and older also share a disproportionate burden of mortality from hematologic malignancies. More than 50% of deaths from AML, CML, CLL, NHL and myeloma are reported in patients 75 years and older. Survival declines with increasing age for most hematologic malignancies. One- and 5-year survival rates among older adults with hematologic malignancies from the SEER database indicate that patients in the 75-84 years age group and ≥85 years age group have lower survival rates than those <75 years of age for all

Journal Pre-proof malignancies with more striking differences in survival rates noted between younger and older adults with acute lymphoblastic leukemia (ALL) and AML [5]. Age related disparities in survival appear to be particularly greater for patients with AML ≥75 years compared to those less than 75 years. [4, 6]. With improved supportive care and approval of several new drugs, survival appears to have improved for adults 65 years and older over the years, but the improvement in survival may be restricted to patients in the 65-74 years age group for some hematologic malignancies. Pulte et

of

al reported-on trends in 5-year relative survival of patients ≥65 years with hematologic

ro

malignancies (ALL, AML, CLL, CML, HL, NHL, and MM) for the periods of 1997-2000, 2001-

-p

2004, 2005-2008, and 2009-2012. Five-year relative survival improved over the time periods for

re

all age groups (65 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years) for most hematologic malignancies evaluated with the exception of patients with AML ≥75 years. No survival

lP

improvement was seen for patients who were 75 years and older with AML. Despite overall improvement in survival over the years, adults ≥75 years of age continue to have lower relative

na

survival than the younger age groups and patients ≥85 years continue to have the lowest

Jo

ur

survival among all age groups [20].

2.0 Consideration of age-related differences in patient and clinical characteristics 2.1 Aging associated changes in physiologic reserve and pharmacokinetics

Aging is associated with physiologic changes in several organ systems that may have an impact on the pharmacokinetics and bioavailability of drugs in older adults [21]. Glomerular filtration declines with increasing age with an estimated decline of 0.75 ml/min per year after 40 years of age [22]. Increase in body fat and decrease in lean body mass can change volume of drug distribution. This decline in muscle mass maintains normal creatinine levels despite declining renal function and as such serum creatinine is not a good predictor of renal function in older

Journal Pre-proof adults. Splanchnic circulation also declines with increasing age. These changes may necessitate adjustment of doses of certain cancer therapies. However, studies have not consistently demonstrated clinically relevant age-related changes in pharmacokinetics (PK) to warrant specific dose recommendations based on age alone for most drugs used commonly to treat hematologic malignancies. Studies with chemotherapeutic agents like doxorubicin, a drug commonly used as part of the CHOP regimen, in the treatment of NHL have reported age-

of

related changes in PK but were not clinically relevant to necessitate dose modification based on age alone [23]. Higher rates of toxicities have been reported in older adults compared to

ro

younger adults even with molecularly targeted agents [24]. However, like the cytotoxic drugs

-p

clinically relevant age-related changes in PK have not been consistently reported for the

re

targeted agents. Age-based dosing recommendations are not included in the prescribing information for most oral cancer therapies approved for treatment of hematologic malignancies.

lP

Although, when information is available, dosing recommendations based on renal or hepatic

na

impairment are included [23, 25] and dose modifications based on renal or hepatic function may be warranted [26]. Enrollment of a representative older patient population may generate data to

Jo

malignancies.

ur

support dosing recommendations applicable to the older adult population with hematologic

2.2 Comorbidities and performance status

Older adults with hematologic malignancies have higher rates of organ dysfunction and comorbidity compared to younger adults. In patients > 80 years of age with NHL, 87% of the patients were found to have at least one comorbidity [8]. In the population-based Eindhoven Cancer registry, comorbidity prevalence correlated with increasing age but not with stage or histology. Comorbidity was reported in 66% of patients >60 with NHL and 58% of patients with HL. In the younger age group (<60 years), only 33% of patients with NHL and 21% of patients

Journal Pre-proof with HD reported any comorbidity [27]. Cardiovascular disease and hypertension were the most common comorbid conditions reported in older patients with HL and NHL. Comorbidity may impact receipt of appropriate treatment for hematologic malignancy in the older adult. In the same study reported above, the presence of co-morbidity was associated with decrease in receipt of chemotherapy in patients with early stage HL and aggressive NHL [28]. Increasing comorbidity in the older adults also has a consequence of increasing polypharmacy and risk for

of

drug interactions that may impact outcomes. In a retrospective study, patients ≥70 years with cancer (14% with lymphoma, myeloma and 20% with other cancers like leukemia) receiving

ro

outpatient chemotherapy had an average of three comorbid conditions and were taking an

-p

average of 9.1 prescription and non-prescription drugs. The study also noted that none of the

re

physicians who responded to a questionnaire made a treatment modification based on potential for drug-drug interaction or PK and pharmacodynamic (PD) data. Inadequate guidance to

lP

modify treatment and interest in maintaining dose as per standard of care were among the

na

many reasons cited by the physicians for not modifying treatment [29]. Adequate enrollment of an older population who are often receiving concomitant medications may generate sufficient

ur

data to make recommendations for treatment modifications for drug interactions.

Jo

Poor performance status is also more common among the older age groups compared to the younger age groups. In the Swedish Leukemia Registry 72% of patients in the 55 to 59-year age group had World Health Organization (WHO) performance status of 0 or 1 compared to only 40% of patients in the 75-79-year-old age group. Worse performance status was associated with increased early death rates regardless of age [30]. Adequate representation of older adults with comorbidities and poor functional status may further refine dosing recommendations to guide treatment modification in this patient subpopulation.

2.3 Aging is a heterogeneous process

Journal Pre-proof Chronologic age ≥65 years is commonly used to define older adults or characterize the subgroup of older patients at increased risk for adverse outcomes from treatment. However, it is well recognized that this arbitrary cut-off may not truly capture the heterogeneity that is inherent within this patient subpopulation. This is evident in the differential outcomes with increasing age subgroups in patients 65 years and older. A SEER analysis [5], reported lower one year and 5year survival rates in patients 85 years and older compared to those in the 75-84 years age group. Median survival was higher in the patients in the 75-84 years age group compared to

of

patients ≥85 years of age for all malignancies studied except for ALL and AML. There was no

ro

difference in survival among the 75-84 years and ≥85 years age group for ALL and AML

-p

patients [5]. While comorbidities and performance status are higher (worse) in the older adults

re

there is substantial variation in their rates in different age subgroups over 65 years. Additionally, chronologic age and traditional assessments of performance status by commonly used indices

lP

like Eastern Cooperative Group (ECOG) performance status or Karnofsky status may not fully

na

capture the heterogeneity in the older patient population with hematologic malignancies. Impairments in physiologic function have been reported in patients with preserved performance

ur

status. For instance, impairments in objective physical performance (short physical performance

Jo

battery <9) was reported in 31% of patients with ECOG PS 0-1 and diagnosis of AML. Comorbidity, impairment in activities of daily living (ADL), instrumental activities of daily living (IADL), distress and cognitive impairment was reported in 40%, 34%, 24%,50%, and 24% of patients with ECOG 0-1 [31]. Frailty or increased vulnerability to stressors due to decline in functional reserve across organ systems can occur as a result of age-related physiologic changes and stressors. Frailty is a complex concept but is commonly defined either in terms of a frailty phenotype or an accumulation of deficits model. Frailty as measured by objective functional parameters has been reported in older adults in multiple hematologic malignancies including AML, CLL, NHL and MM [32, 33]. Presence of frailty may vary within the older age subgroups; such that while

Journal Pre-proof one 75-year-old may be fit and may experience a treatment outcome similar to a patient ≤65 years after treatment; a frail counterpart of the same age may experience significant treatmentrelated toxicity. Using traditional prognostic variables including age, performance status, type of therapy, and geriatric assessments (ADL, IADL and Charlson comorbidity index (CCI)); Palumbo et al. characterized 869 older patients with newly diagnosed MM at risk for poor OS into three groups: frail (additive total score ≥2), intermediate fitness (score=1) and fit (score=0).

of

Less than 20% were assessed as frail (total score) based on age alone, however nearly 50% of those identified as frail were >80 years of age [34]. At 12 months, the cumulative incidence of

ro

Grade 3-4 toxicity and treatment discontinuations were higher in patients classified as frail

-p

(34%, 31%) compared to those classified as intermediate fitness (26%,21%) and fit (22%,16%)

re

respectively. In a prospective study of patients with AML undergoing intensive chemotherapy, impairments in individual geriatric domains assessed was noted in 20%-70% of patients. Overall

lP

survival was lower in patients with poor cognitive function (100-point Modified Mini-Mental

na

State<77) and low physical function at baseline, i.e. short physical performance battery (SPPB) score <9 compared to patients who had higher scores. Neither comorbidity, ECOG performance

ur

status, or age was associated with OS in this study [35]. Similarly, in a study of patients with CLL undergoing treatment with low dose fludarabine, impairment in cognition and physical

Jo

function as assessed by the ‘timed up and go’ test was associated with poor overall survival whereas comorbidities as assessed by the Cumulative Illness Rating Scale and instrumental activities of daily living (IADL) were not associated with survival [36]. Assessing frailty or “physiologic age” in older patients with hematologic malignancies via multidimensional geriatric assessment may identify patients who can tolerate intensive treatment and have improved survival, and can add to information obtained from evaluating comorbidities, performance status, or age alone in isolation. Enrollment of older adults who are both fit, and frail could allow evidence generation to guide treatment decisions in heterogeneous older patients with

Journal Pre-proof hematologic malignancies. However, there is a lack of consensus on the definition of frailty or measures to assess frailty in the hematologic malignancies.

2.4 Differences in tumor biology

Age related differences in tumor biology have been reported in hematologic malignancies, most

of

commonly in AML. Older patients with AML have greater rates of adverse cytogenetics and multidrug resistance protein expression [37]. In a retrospective analysis of 968 patients with

ro

AML enrolled in 5 southwest oncology group trials, multidrug resistance was found in 33% of

-p

patients younger than 56 compared to 57% of patients 75 years and older. The percentages of

re

favorable cytogenetics and unfavorable cytogenetics were 17% and 35% in patients younger than 56 years compared to 4% and 51% in the 75 year and older patients with AML [38].

lP

Monosomal karyotype also more frequently identified in older adults with AML is associated with

na

poor prognosis [39]. In an analysis of over 3000 patients from German Hodgkin lymphoma trials that enrolled 372 (9%) patients older than 60 years, older patients had higher rates of B

ur

symptoms (50% v 43%), elevated erythrocyte sedimentation rate (59% v 51% ), mixed

Jo

cellularity subtype (35% v 19%), and poorer performance status (Karnofsky performance score < 80: 11% v 3%) compared to younger patients [40). Similar differences have also been reported in other HL studies [41]. In DLBCL, a higher prevalence of the activated B cell (ABC) subtype, a molecular subtype associated with adverse prognosis, has been reported in older adults [42]. These differences in disease-related characteristics highlight the need for adequate representation of older adults in clinical trials. However, differences in tumor biology between younger and older adults have not been reported consistently in all hematologic malignancies.

2.5 Inadequate treatment of older patients with hematologic malignancies

Journal Pre-proof Inadequate representation of older adults in clinical trials may lead to inadequate treatment of older patients with hematologic malignancies. Age alone is often the only factor used to guide treatment decisions. In patients with newly diagnosed diffuse large B cell lymphoma, the proportion of patients receiving first-line chemotherapy declined with age from nearly 95% in patients 65 years and older in those <65, to just 67% in those over 75. Similarly, the percentage of newly diagnosed patients receiving chemotherapy decreased from 77% in those under 65

of

years to around 50% in patients 75 years and older [43]. In a SEER-Medicare analysis of patients with AML 65 years and older, only 7.5% of patients 65-69 years were not treated with

ro

any therapy within three months of diagnosis, compared to 55% of patients ≥85 years of age.

-p

Additionally, patients ≥85 without comorbidity (CCI score of 0) received therapy three times less

re

than patients in the 65-69-year age group without comorbidity [44]. Older patients also are less likely to receive intensive chemotherapy despite studies indicating benefit from intensive

lP

treatment [28, 45, 46]. In a SEER Medicare database analysis of over 2000 older adults with AML, the odds of receiving cytotoxic chemotherapy within 2 years of AML diagnosis was lower

na

in the 75-84 years and ≥85 years age group compared to patients in the 65-74-year age group.

ur

Survival improvement with treatment was noted in all age groups [46]. Undertreatment can

Jo

result in poor survival in the older patient population [47]. However, use of standard doses inadequately tested in the older population may also not be appropriate in older patients where there is significant heterogeneity with respect to treatment tolerance. Higher rates of treatment related myelosuppression, grade 3 or 4 infections, pulmonary and cardiac toxicity have been reported in older patients (≥60 years) compared to younger patients treated on the German Hodgkin’s Study Group trials. Despite receiving appropriate doses of therapy and achieving response rates comparable to younger patients, survival was lower in the older patients compared to younger patients. More intensive regimens did not improve outcomes in older patients compared to standard multiagent chemotherapy regimens [40].

Journal Pre-proof 3.0 Current state of participation of older adults in hematologic malignancy trials

Several publications have reported on disparities between participation of older patients in cancer clinical trials compared to the proportion of older adults with cancer in population-based registries. However, hematologic malignancies comprised only a small proportion of the total study population evaluated in these studies. When reported, enrollment rates for patients 65

of

years and older for malignancies broadly classified as leukemia, lymphoma and MM trials were

-p

enrollment rates in patients 75 years and older.

ro

commonly reported (Table 1). Few publications on hematologic malignancies commented on

re

3.1 Participation of older adults in cooperative group or research organization database

lP

Three publications have reported enrollment rates in the older age groups in NCI sponsored

na

cooperative group trials in the U.S. The proportion of patients enrolled were compared to the incidence rates of specific hematologic malignancies in the SEER database. In the earliest

ur

publications, Trimble et al in 1994 published on enrollment rates in in the NCI-sponsored

Jo

cooperative group phase II and phase III leukemia trials compared to rates to SEER 1990 age and sex specific incidence. Only rates in rates in older male patients with leukemia were reported. Less than 10% of patients enrolled on the leukemia trials were older than 65 years compared to nearly 55% in this age group in the SEER population [48]. Hutchins et al reported participation of over 16,000 patients in the Southwest Oncology Group clinical trials from 1993 to 1996. Overall, 25% of the population enrolled were 65 years and older compared with 63% of cancer diagnosed in this age group in the U.S. population in the SEER database for the period from 1992 through 1994. Only 25% and 27% of the population enrolled onto the MM and leukemia trials were 65 years and older compared to 70% and 63% of patients with the respective cancer diagnosis reported to the SEER database. In the lymphoma

Journal Pre-proof trials, the rates of representation of the 65 years and older patients appeared to mirror the SEER incidence rates [49]. Similarly, Lewis et al reporting on participation of older adults in 495 NCI-sponsored, cooperative group trials from 1997 through 2000 noted that patients 65 years and older were underrepresented in the phase II and III leukemia, lymphoma and myeloma trials compared to the proportion of ≥65 years patients with the respective cancers in SEER. [50]. Participation rates for older adults was not different by trial phase (phase II versus III) for

of

lymphoma. Phase II myeloma trials enrolled a greater proportion of older adults (~68%) compared to phase III trials (30%) whereas the reverse was true for leukemia (~25% vs 55%)

ro

trials. The reasons for these differential enrollments by phase and tumor type are unclear.

-p

Lower participation of older adults in hematologic malignancies does not appear to be limited to

re

trials conducted in the US. Yee et al reported-on enrollment of older adults from over 4,000 patients in 69 trials evaluating 16 cancer types in the National Cancer Institute of Canada

lP

Clinical Trials Group (NCI-CTG) [51]. Disparities were again noted in the proportion of older patients enrolled onto the leukemia and lymphoma trials. For the trials in lymphoma, only 2%

na

(4/169) were ≥65 years in the NCI-CTG lymphoma trials compared to 45% of lymphoma

ur

cancers in Canada. There was only a small difference in the percentage of patients ≥65 years

Jo

enrolled in NCI-CTG (63%) compared to the proportion of patients ≥65 years diagnosed with multiple myeloma in the Canadian population (~69%). However, the analysis was based on only one myeloma trial available at that time. Differences in enrollment between the SWOG trials reported by Hutchins et al and the NCI-CTG trials conducted during the same period were noted by Yee et al in the same publication. In the Hutchins study, older adults with lymphoma appeared to be well represented in the SWOG trials compared to the SEER proportion of cancers whereas in the NCI-CTG trials there was a significant disparity between the older adults enrolled in lymphoma trials compared to the Canadian population with lymphoma. One publication reported participation rates in a specific hematologic malignancy, AML. In a large nationwide population-based study among >12,000 adult patients with a diagnosis of AML

Journal Pre-proof in the Netherlands Cancer Registry (NCR) from 1989 to 2012, clinical trial participation rates in Haemato Oncology Foundation for Adults in the Netherlands (HOVON) or European Organization for Research and Treatment of Cancer (EORTC) trials when a trial was open for accrual in Netherlands during this 24-year period was 68%, 57%, 30% and 12% for patients with AML 18–40, 41–60, 61–70 and >70 years of age, respectively. The proportion of patients diagnosed with non-APL AML in the four age groups (18–40, 41–60, 61–70 and >70 years)

of

overall was 10%, 10%, 23%, 22% and 40% respectively. Despite low rates of enrollment in the > 70 years age group in trials, 35% of patients >70 years not entered onto the trial received

-p

ro

intensive therapy in the form of chemotherapy or stem cell transplantation [52].

re

3.2 Participation of older adults in hematologic malignancy trials submitted to regulatory

lP

agencies to support drug approvals

na

Analysis of trials included in applications submitted in support of product approvals also have demonstrated disproportionate numbers of adults 65 years and older in hematologic malignancy

Jo

diagnosis.

ur

clinical trials compared to proportion of patients with reported diagnosis of hematologic

Talarico et al reported a retrospective analysis of trials submitted to FDA to support approval of new or supplemental indications for hematologic cancers from 1995 to 2002 [53]. Of the 55 registration trials included for analysis, 11 were leukemia trials evaluating drug regimens for the treatment of chronic myelogenous leukemia, acute promyelocytic leukemia, acute myelogenous leukemia and 2 were trials for cutaneous T cell lymphoma. In the SEER database, incident diagnosis of leukemia was reported in 55% of patients 65 years and older, however, patients 65 years and older comprised only 20% of patients enrolled in leukemia registration trials. Similarly, 70% of incident lymphoma diagnosis in the SEER database was reported in patients ≥65 years, however they comprised only 20% of patients in lymphoma registration trials submitted to the

Journal Pre-proof FDA. Lower enrollment rates of older adults in Japanese registration trials compared to proportion of older adults with cancer was reported by Yonemori et al [54]. The analysis was based on registration trials conducted in Japan and overseas and reviewed by the Pharmaceuticals and Medical Devices Agency, Japan (PMDA) between 1999 and 2008. Of the 234 registration trials (78 in Japan and 156 overseas), 48 trials were conducted in hematologic malignancies. The median age of patients in trials of hematologic malignancies reviewed by

of

PMDA was more than 10 years lower than the median age of the Japanese cancer population. For two hematologic malignancy trials (1 in myeloma and 1 lymphoma) the proportion of

ro

patients 65 years of older in the trials was compared to the patients with these cancers in the

-p

Japanese population. Patients 65 years and older comprised 46% of the single regis tration trial

re

for MM in Japan compared to 78% of patients ≥65 years with myeloma in the Japanese population, whereas no patients ≥65 years were reported enrolled on the lymphoma trial [54].

lP

Hori et al analyzed reviews and summaries of data on the internet for 68 clinical trials in 43

na

applications submitted for approval of cancer drugs to the PMDA. With few exceptions, the median age of patients enrolled in cancer clinical trials was lower than the median age of the

ur

overall cancer population. The median age of participants in lymphoma clinical trials for

Jo

rituximab ranged from 52-63.7 years compared to the median age of 69 years in the lymphoma cancer population. The median age for CML trials of imatinib ranged from 46-50 years compared to a median age of 66 years for CML population in Japan. In the 6 trials for acute leukemia, a 20-year difference was noted in the median age of the participants enrolled in the clinical trials (lower median age in trials) compared to the median age of leukemia in the Japanese cancer population [55]. As noted earlier, a significant proportion of hematologic malignancies are diagnosed for the first time in adults ≥75 years. Few retrospective analyses have reported on participation of adults 75 years and older in hematologic malignancy trials. In the analysis of leukemia trials by Trimble et al only 2% of male patients enrolled on leukemia trials were ≥75 years compared 28% of male

Journal Pre-proof leukemia patients in the SEER population [48]. A recent FDA analysis published in an abstract form which reported on rates of older adult participation in > 200 hematologic malignancy trials submitted to FDA in support of approval of new or supplemental indications for hematologic cancer therapies from 2005-2015 [56]. Clinical trial participation was very low in the 75 years and older age group compared to SEER new cases in this age group with nearly 20% difference between clinical trial participation and proportion of new cases in SEER. While nearly 40% of

of

new cases of CLL were diagnosed in patients ≥75 years, only 16% of patients are enrolled onto clinical trials. Only 13% of clinical trial participants in the MM trials were over age 75 compared

ro

to 33% of new cases of multiple myeloma in patients ≥75 years in SEER. Patients 75 years and

-p

older comprised 9% of the lymphoma trial participation compared to 28% of SEER incident

re

cases. The largest disparity was in the CML trials; only 3.8% of the clinical trial participants were 75 years and older compared to 28.6% in SEER. Interestingly, in this analysis there were no

lP

disparities noted in rates of clinical trial participation for older adults with MM, CLL and lymphoma in the 65-74 years age group of patients and proportion of new cases reported in the

na

SEER registry for the respective disease. In the lymphoma subset, data from Hodgkin’s and

ur

non-Hodgkin’s lymphomas were pooled and may have resulted in a biased estimate against the

Jo

older age groups as the Hodgkin’s trials may have enrolled a slightly younger population. The percentage of patients on the clinical trials was higher than the SEER incident cases in 65-74 years age group for CLL trials. The reason for higher enrollment of patients in the 64-75-year age group is not entirely clear.

4.0 Barriers to enrollment of older adults 4.1 Restrictive Protocol Eligibility Criteria

Few studies in literature focused primarily on reasons for low enrollment of older adults in hematologic malignancy trials. In the publications that reported on barriers to enrollment in

Journal Pre-proof hematologic malignancy trials, restrictive eligibility criteria either due to inclusion of upper age limit, restrictions on comorbidities and requirements for a minimum performance status appear to be commonly reported barriers to enrollment. Ineligibility for hematologic malignancy trials due to restrictive eligibility criteria appear to range from 50% to as high as 70%. Upper age limit definitions for enrollment are often included in hematologic malignancy trials particularly in trials evaluating intensive chemotherapy in AML and trials for transplantation eligible patients in MM

of

[57, 58] without any clear justification for exclusion based on chronologic age alone. In an analysis of patients in acute leukemia trials, reasons for exclusion for 50% of patients of the

ro

AML and ALL patients was being due to age outside the limits specified in the protocols [59]. In

-p

an analysis of ongoing phase I, II, and III hematologic malignancy trials identified through a

re

National Institute of Health (NIH) search in 2013, Hamaker et al reported that 827 (70%) of total 1,207 trials excluded older patients, and 12% of these excluded older adults primarily due to

lP

restrictions on upper age limit (requirement for ≤75 years). Leukemia, myelodysplastic

na

syndrome, and myeloproliferative disorder trials were more likely to have exclusions based on an upper age limit [60]. In a systematic review evaluating barriers to enrollment of older adults in

ur

NHL trials; 28% of age non-specific trials directly excluded patients >65 years (maximum age

Jo

requirement of 59, 60 or 65 years). In 13 RCTs the maximum age was 59–60 years, in 9 RCTs the age limit was 61–65, 69–70 years in 12 RCTs, 75–79 years in 8 RCTs, and 80 in 1 RCT [61].

In recent years, enrollment barriers due to restrictions based on specific upper age limits have declined whereas restrictions based on organ function, comorbidities and concomitant medications may be increasing [58, 62]. The U.S. FDA published a review of eligibility criteria of 297 oncology protocols including 18 protocols for lymphoma, 12 in acute leukemia, 10 in MM, and 24 evaluating multiple hematologic malignancies. Ninety-five percent of the adult protocols did not include a specified upper limit for age but nearly 95% of the 284 adult oncology protocols specified a performance status requirement. Only two protocols included patients with an ECOG

Journal Pre-proof PS of 0 to 3 with the remainder mandating a requirement of ECOG PS of 0 or 1 or ECOG PS of 0 to 2 (or equivalent Karnofsky PS) and nearly 50% had requirement for minimum life expectancy. Requirement for laboratory tests of organ function as an eligibility requirement was included in almost all protocols. Even among hematologic malignancy protocols like lymphoma where disease related cytopenia are common, some protocols required absolute neutrophil count ≥1000/µL for eligibility [63]. Several other analyses have reported restrictive eligibility

of

criteria related to performance status as possible reasons for non-inclusion of older adults in hematologic malignancy trials. In the analysis of phase I, II, and III hematologic malignancy

ro

trials by Hamaker et al, in addition to exclusion based on upper age limits, 31% excluded older

-p

patients based on restrictions due to strict organ function requirement, 4% were excluded based

re

on performance status restrictions, and 23% were excluded based on combination of age, performance status or organ function restrictions[60]. The proportion of trials excluding older

lP

patients ranged from 56% for CLL trials to nearly 88% for ALL trials. High rates of exclusion due

na

to presence of comorbidities (90%) from hematologic malignancy trials were also reported in a study of over 9,000 patients in the WHO International Clinical Trials Registry Platform [58]. The

ur

most common comorbid diseases specified for exclusion were renal failure (71%),

Jo

cardiovascular disease (66%) and infectious disease (57%). Other eligibility criteria restrictions included presence of at least one abnormal laboratory result (81%), the use of one or more specific drugs (67%), and upper age limit (41%). A systematic review of barriers to enrollment of older adults in NHL trials reported that 54% of the total 87 trials identified had excluded older adults due to requirement for Eastern Cooperative Oncology Group (ECOG) PS < 2, creatinine clearance above a predefined threshold value, or absence of comorbidity (heart or pulmonary diseases, strokes, or reduced mobility)[61]. Eligibility criteria restrictions may not be exclusive to trials evaluating chemotherapy, but eligibility restrictions may also be present in trials evaluating molecularly targeted therapy [64].

Journal Pre-proof While some restrictions in eligibility criteria are important to safeguard patients and maintain internal validity, the evidence that these restrictions in eligibility criteria may necessarily reduce toxicity is not clear. In a study of 97 randomized controlled trials of leukemia, lymphoma, MM, myelodysplastic syndromes, or myelofibrosis; hepatic, cardiac or renal eligibility criteria did not reflect the expected toxicities based on known or expected toxicities from prior experience with the drug. Eligibility criteria for hepatic and renal function also did not correlate with observed

of

toxicities in the trials [65]. Similarly, no differences in serious adverse reactions were seen between trial eligible and trial ineligible patients with MM in the Connect MM Registry [66].

ro

Additionally, although comorbidities, organ impairment, and poor performance status [8] are

-p

thought to contribute to increased toxicity from cancer therapies in the older adults, this has not

re

been consistently demonstrated in trials of hematologic malignancies [67]. Poor outcomes may be as much from decreased treatment than the actual comorbidities or poor performance status

lP

itself [68, 69]. Additionally, comorbidities and performance status alone are poor predictors of

na

treatment toxicity and may not fully capture the heterogeneity present in the older adult population with hematologic malignancies [70].

ur

Expansion of clinical trial eligibility criteria related to organ function criteria and functional status

Jo

may lead to higher participation of older patients in clinical trials [50]. Lewis et al reported that relaxing exclusion criteria based on organ function (cardiac, hematologic, pulmonary and hypertension) and functional status could increase enrollment of older adults in the clinical trials included in their analysis by 47% and 60% respectively. Recent drug approvals in hematologic malignancies indicate that it is possible to enroll older adults including those with comorbidities in drug approval trials. Glasdegib in combination with low dose cytarabine and venetoclax in combination with azacytidine or decitabine or low dose cytarabine were approved for the treatment of newly diagnosed patients with AML who are 75 years and older or who have comorbidities that preclude intensive chemotherapy. In the phase III trial that supported the approval of glasdegib, the median age of patients was 77; 61% of patients were 75 years and

Journal Pre-proof older, 51% enrolled had ECOG PS of 2, 45% had at baseline severe cardiac disease and 17% enrolled had a serum creatinine >1.3 mg/dL [71]. In the two trials supporting approval for venetoclax in combination with azacitidine or decitabine or venetoclax with low dose cytarabine, the median age of the trial participants was 76 years [72]. Seventy percent and 75% of the overall study participants in the venetoclax with hypomethylating agents’ trial and venetoclax with low dose cytarabine trial respectively, were either 75 years and older or had comorbidities

of

that precluded intensive chemotherapy administration [72]. Ibrutinib was approved for patients with newly diagnosed CLL based on a randomized phase III trial of patients with newly

ro

diagnosed patients 65 years and older with CLL. Thus, it may be possible to remove restrictions

-p

to eligibility criteria and still ensure safety of the patient population and maintain the scientific

na

lP

4.2 Patient and physician related barriers

re

validity of the trial [73].

Little is known about the attitudes of physicians and older patients towards enrollment in

ur

hematologic malignancy trials. Majority of this information is obtained from studies in solid tumor

Jo

populations or hematologic malignancy populations that included both younger and older adults [74]. Patient refusal accounted for less than 5% of reasons for non-enrollment in phase III trials for acute myeloid leukemia [75]. Other reasons including lack of knowledge of an available trial for participation or lack of a suitable trial (perceived lower toxicity) [59] may influence older adult participation in hematologic malignancy trials [76]. In a large systematic meta-analysis, Unger et al reported that nearly 50% of patients did not have an available trial for their cancer type and stage [77]. Yee et al, pointed out that the differences in accrual rates; higher for lymphoma trials and lower for the leukemia and myeloma in the SWOG trials compared to the NCI-CTG trials mentioned previously may have been be in part due to differences in the number and types of studies that were available in the two countries at the time as well as the suitability of

Journal Pre-proof the available trial for older adults [51]. The type of trial design, randomization, [59] and endpoints assessed have also been reported as possible barriers for clinical trial enrollment for older adults with hematologic malignancies [78]. In a survey of 1066 patients, including 195 patients (20%) with hematologic malignancies, greater than 90% were willing to participate in a trial [79]. However, only 50% agreed to participate if the treatment was chosen at random. Older participants reported a higher willingness to participate if additional information regarding the

of

two treatments in the randomized study was given to them and there was a choice to leave an unsuitable study and receive alternate treatment [51, 78]. Other reported barriers that may

ro

influence patient participation include distance of clinical trial site from patient’s home [80],

-p

difficulties in transportation [81] and lack of adequate insurance [82, 83]. However, having

re

insurance or coverage alone may not be sufficient to increase clinical trial participation of older adults in cancer clinical trials [50, 51]. Understanding the risks and benefits of the treatments

na

patients in cancer clinical trials.

lP

they are receiving [79] and improving access to clinical trials may improve enrollment of older

Restrictive eligibility criteria also appear to be a major barrier for physicians to enrolling older

ur

cancer patients on to cancer clinical trials [75, 84]. Physicians may be unwilling to discuss a trial

Jo

or enroll a patient because of patient’s age [85, 86]. Nearly 50% of 437 physician members of the Illinois Cancer Center (ICC) surveyed stated that they excluded patients from clinical trials on the basis of age [86]. Thirty percent of Canadian physicians (70% of whom were hematologists and oncologists) surveyed reported presence of comorbidities as one of the major reasons for non-inclusion of older adults in cancer clinical trials. Concerns for increased toxicity was reported by 50% of physicians in this survey and 25% reported patient and family preferences as a reason for not enrolling older adults. Additionally, logistical issues such as long distance to the clinical trial treatment center, time required for enrollment and follow up, and complexity of the clinical protocol are other reasons reported for physician reluctance to enroll older adults in cancer clinical trials [51, 84]. Physicians may be willing to include patients’ older

Journal Pre-proof adults in trials if they perceive the study and the aims are scientifically sound and will contribute to medical progress. A survey of 99 physicians participating in Nordic multicenter trial of MM reported scientific purpose as the most important reason for enrolling patients onto a clinical trial, followed by simplicity of the protocol, ethical aspects of the study, communication with study organization and other investigators, and limited impact of the study on their workload for enrollment in the multiple myeloma trial [87]. However, this survey was not designed to assess

of

barriers specific to enrollment in older adults. Physician lack of awareness of trials appropriate

ro

for the older patient may prevent them from considering older patients for trial enrollment [82].

-p

5.0 Approaches to address underrepresentation of older adults in hematologic malignancy trials

re

5.1 Overarching strategies

lP

There has been a concerted effort from multiple stakeholders such as industry, advocacy

na

groups, the FDA, and other governmental organizations to encourage inclusion of older patients in cancer clinical trials including hematologic malignancy trials. The institute of Medicine (IOM)

ur

[88], American Society of Clinical Oncology (ASCO) [89], Cancer and Aging Research Group

Jo

[90, 91, 92], National Institute on Aging, and National Cancer Institute (NCI) [93] have all recognized the knowledge gap in treating older adults with cancer, conducted conferences highlighting the need for evidence, and issued recommendations to address the issue of underrepresentation of older adults in cancer clinical trials. The 21st Century Cures Act Section 20138 —signed into law in December 2016—requires NIH to address the inclusion of patients over the entire life span including older adults, to require justification for any age-related exclusions, and include data on the inclusion of participants in clinical trials by age. NIH policy for 2019 states that researchers should include a rationale for selecting the age range and provide justification for any exclusions based on age.

Journal Pre-proof 5.2 Broadening eligibility criteria

Restrictive eligibility criteria are major barriers to the enrollment of older adults to cancer clinical trials. Re-evaluating exclusion criteria related to comorbidities was one among the two top strategies reported in a web‐based survey of Alliance for Clinical Trials in Oncology (“Alliance”) members. Multiple stakeholders including the FDA have advocated a more rational approach to

of

eligibility criteria in cancer clinical trials, while maintaining standards for safety. Recently, the FDA Office of Hematology and Oncology Products along with other stakeholders

ro

participated in a series of working groups organized by ASCO and Friends of Cancer Research

-p

to examine eligibility criteria in cancer clinical trials. The findings and recommendations of the

re

eligibility criteria working groups were published in a series of articles in 2017 [94, 95]. Organ dysfunction, prior or concurrent malignancies, and comorbidities working group

lP

recommendations are summarized below.

na

The working group recommended considering broadening organ function criteria to enroll patients with creatinine clearance values ≤30, mild or moderate hepatic dysfunction or patients

ur

with cardiovascular dysfunction if available data (non-clinical, clinical, PK/PD data) indicate that

Jo

it may be safe to include these patients. Additionally, dose modification guidance for patients that permit safe administration of these drugs in these patients should also be considered. The organ dysfunction, prior or concurrent malignancies, and comorbidities working group recommended conservative approach for cardiac function; appropriate exclusion of patients with ejection fraction (EF) less than 35% to maintain patient safety but stated that EF alone should not be used to exclude patients. Trials could also include risk assessment for cardiac failure based on validated clinical heart failure risk system to assess eligibility to clinical trials. The group also called for revaluating QTc criteria and the requirement for ECG monitoring in later phase trials if this was not identified as a concern based on data from first in human studies. The working group on organ dysfunction, comorbidities and prior or concurrent malignancy

Journal Pre-proof noted that inclusion of patients with out of range laboratory tests may be appropriate if these are due to involvement of the related organ by the hematologic malignancy. Collection of baseline comorbidity and functional measures for patient population enrolled in the clinical trial was recommended to help guide treatment decisions for older patients. Measures other than performance status to better assess patient fitness for eligibility onto a clinical trial was also recommended [94]. Regarding inclusion of patients with prior or concurrent malignancies;

of

inclusion of patients with prior or concurrent malignancy could be considered if patients were treated for prior malignancy successfully at least 2 or more years ago or if concurrent

ro

malignancy is stable and does not require disease specific treatment.

-p

Under Section 610 (a)(1) of the Food and Drug Administration Reauthorization Act (FDARA) of

re

2017 FDA also convened a public meeting to evaluate clinical trial eligibility criteria and published a report within 90 days with a summary of topics discussed at the workshop. The

lP

workshop report highlighted several issues including the role of restrictive inclusion and

na

exclusion criteria in clinical research with respect to enrollment of several populations including enrolling older adult population, barriers to enrollment and proposed strategies to address these

ur

issues [96]. Strategies proposed by participants at the workshop to increase enrollment included

Jo

1) transparency in determination of eligibility criteria, 2) patient involvement, 3) gerontologist involvement when designing trials that anticipate enrolling mostly older adults to address needs of the patient population, 4) increasing the use of alternative study designs including open label safety studies to supplement data from phase III trials, 5) use of innovative trial designs like master protocols, and 6) enrolling a broader population with methods to conduct primary analysis in a pre-specified subset of the population. The FDA Office of Hematology and Oncology Products and ASCO along with multiple stakeholders including the pharmaceutical industry, EMA and Centers for Medicare and Medicaid Services held a workshop in 2018 focused on addressing issues related to the limited evidence-based information available for older adults with cancer [97]. The workshop white

Journal Pre-proof paper published subsequently reported on future considerations to increase representation of older adults in cancer clinical trials. A few strategies espoused in the paper include; need for innovative trial strategies including addition of a parallel arm enrolling older adults to a phase III trial and incorporating endpoints that focus on function and quality of life in these trials. The report commented on barriers beyond eligibility criteria that may impact enrollment of older adults including logistical challenges like frequent study visits and access to trials and the need

of

to understand potential barriers to recruitment. Other strategies proposed in the paper included physician and patient education efforts to enhance participation, and potential use of real-world

ro

evidence (RWD) to enhance available data in older adults treated for cancer.

-p

Over the years, the FDA actively implemented regulations, published guidance on enrollment of

re

older adults in clinical studies to enhance participation of a representative population of older adults in clinical trials including cancer clinical trials.

lP

The 1989 guidance for Industry “Study of Drugs Likely to be used in the Elderly,” states that

na

patients included in clinical studies should reflect the population that will ultimately receive the drug. For drugs likely to be used in older adults a reasonable number of older adults should be

ur

included in these clinical trials [98]. Arbitrary exclusions based on age alone, or presence of

Jo

concomitant illness or treatments should be avoided, and sponsors should attempt to include patients 75 years and older including those with comorbidities and concomitant treatments unless there is a concern for patient safety or interpretation of study results. The guidance also stated that older adults preferably should be included in the same trials with younger patients to allow for direct comparisons within the same study among the different age groups. In 1993, the ICH E7 Guideline, “Studies in support of special populations: geriatrics,” was developed within the Expert Working Group (Efficacy) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in an effort to harmonize drug development in the older adult population in Europe, Japan, and the U.S. The updated 2012 ICH E7 FDA guidance for industry published in a question and answer format

Journal Pre-proof underscored that clinical studies enroll a representative population of older adults and recommended that data in a marketing application to be presented in various age groups including 75-84 years of age and 85 years and older [99]. The 2012 Guidance also reiterated several recommendations from the prior FDA guidance in 1989 including, enrolling patients with concomitant illness, avoiding arbitrary upper age limit cut-offs in the inclusion criteria and evaluating pharmacokinetics of drugs over the entire spectrum of the older adult patient population in separate PK study (Table 2).

of

The draft FDA guidance, “Cancer Clinical Trial Eligibility Criteria: Patients with Organ

ro

Dysfunction or Prior or Concurrent Malignancies Guidance for Industry,” [100] provides

-p

recommendations on eligibility criteria considerations for sponsors conducting trials evaluating

re

cancer therapies (Table 3). A draft guidance for industry, “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs,” was issued in

lP

response to Section 610 (a)(1) of the Food and Drug Administration Reauthorization Act

na

(FDARA) of 2017 FDA. The draft guidance discusses broadening eligibility criteria, improving trial recruitment to enroll a representative patient population most likely to use the drug [101]. In

ur

addition to several recommendations regarding community outreach, patient and patient

Jo

advocacy group involvement and participant education about clinical trial participation, the guidance also recommends considering the burden of the planned visit schedule during study design planning. Flexibility in visit windows, reduced frequency of study visits, and use of electronic communication or mobile technology tools may be considered to replace site visits and provide investigators with real-time data.

5.3 Other Considerations

As noted earlier inadequate information on drug effects in the older adults may be a barrier to enrollment of older adults onto clinical trials by physicians. In addition to encouraging enrollment

Journal Pre-proof of a representative older adult population, the FDA has also taken steps to communicate information on the safety and effectiveness of drugs in the older adults including drugs used in the treatment of hematologic malignancies. Under FDA regulations, new drug applications must include effectiveness and safety data presented by gender, age, and racial subgroups and, when appropriate, other subgroups of the population of patients treated, such as patients with renal failure or patients with different levels of severity of the disease (21 CFR 314.50(d)(5)(v)).

of

The “Geriatric Use” subsection of the drug U.S. prescribing information (USPI) includes available information about drugs efficacy and safety in the older adults, compared with younger

ro

adults. The Guidance for Industry Content and Format for Geriatric Labeling” provides guidance

-p

on the type and extent of information to be included in the “Geriatric Use” subsection of the drug

re

USPI. The Drug Trials Snapshots initiative developed in response to the Food and Drug Administration Safety and Innovation Act (FDASIA) Section 907 Act of 2012 [102] to enhance

lP

transparency and provide physicians and patients information regarding clinical trial participation

na

demographics. As part of the Drug trial snapshot [103] FDA makes available information about the trial populations and highlights descriptive differences in efficacy and toxicity among age

ur

groups, sex or race. This may help with decisions regarding participation in future clinical trials

Jo

of similar drugs. However, it is important to note as the numbers of patients in the different subgroups are small, meaningful comparisons and conclusions cannot be made, underscoring the need to enroll sufficient number of patients in the different age subgroups. Additionally, patient focused drug development (PFDD), is an important initiative undertaken by the FDA. FDA over the recent years has issued guidance [104] and held workshops/meetings to gather patient input on their disease and treatments. Patient reported measures of physical function, symptomatic side effects, and disease related symptoms from well-designed trials have been used to support traditional efficacy endpoints and are included in the USPI. For instance, the label for Jakafi (ruxolitinib) includes details on reduction in myelofibrosis total symptom score, a

Journal Pre-proof co-primary endpoint in the double-blind, randomized, placebo-controlled study that supported the U.S. FDA approval of the drug [105].

6.0 Future considerations

As the median age at diagnosis for most hematological malignancies is 65 years or older and a

of

significant proportion of patients diagnosed are 75 years and older; new and current cancer therapies that are approved are likely to be used in these patient groups. Available evidence

ro

indicate that enrollment rates in hematologic maligancy trials continue to remain low for older

-p

patients, particularly for those adults 75 years and older. Representation of these patients in

re

hematologic maligancy trials may increase our knowledge about the treatment effects of cancer therapies in the older adult population. However, several barriers to enrollment exist and

lP

extensive collaboration is required to incorporate and evaluate the success of current strategies

na

such as broadening eligibility criteria to enhance enrollment of older adults with hematologic maligancies in clinical trials. These approaches are needed to resolve residual uncertainties in

Practice Points 

Jo

ur

the care of older adults with hematologic malignancies.

Older adults including adults ≥75 years make up a significant proportion of patients with hematologic malignancies



Age related differences in patients and clinical characteristics exist in patients with hematologic malignancies



Chronologic age and traditional performance status assessments cannot fully capture the inherent heterogeneity that exists in the older adult population with hematologic malignancies

Journal Pre-proof 

Restrictive eligibility criteria appear to be commonly reported barrier to enrollment of older adults in hematologic malignancy trials similar to solid tumor trials



There is minimal evidence suggesting older adults are less likely to participate in available hematologic malignancy trials



Enrollment of a representative older adult population in hematologic malignancy trials may

of

permit generalizability of trial results to population with hematologic malignancies

Research Agenda

Evaluate impact of incorporating eligibility criteria recommendations in hematologic

ro



Innovative trial designs and analysis that allows enrollment of older population with

re



-p

malignancy trials and increase in participation of older adults specifically patients ≥75 years



Including novel assessments to assess function and fitness of older adults enrolled in

na

hematologic malignancy trials 

lP

comorbidities or frailty

Incorporate endpoints that assess physical function and improvement in disease and

ur

treatment-related symptoms in hematologic malignancy trials in addition to traditional



Jo

disease assessment efficacy endpoints Assess feasibility of using real world data to answer questions on safety and efficacy of approved hematologic cancer drugs in older adults 

Increase participation of patient and advocacy groups to enhance enrollment of older adults

Conflict of Interest Statement The authors have no conflicts of interest to declare.

Journal Pre-proof Acknowledgements

Jo

ur

na

lP

re

-p

ro

of

The authors received editorial support during manuscript development from Kirsten Goldberg.

Journal Pre-proof References

Jo

ur

na

lP

re

-p

ro

of

1. SEER Cancer Statistics Review. National Cancer Institute. 1975-2014. Available from: https://seer.cancer.gov/csr/1975_2014/ 2. Collaboration GBoDC. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease StudyGlobal Burden of Cancer, 1990 to 2016Global Burden of Cancer, 1990 to 2016. JAMA Oncol. 2018;4(11):1553-68. 3. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758-65. 4. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued imp rovement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-8. 5. Krok-Schoen JL, Fisher JL, Stephens JA, Mims A, Ayyappan S, Woyach JA, et al. Incidence and survival of hematological cancers among adults ages >/=75 years. Cancer Med. 2018. 6. Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer. 2013;119(15):2720-7. 7. Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, et al. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the intergroupe francophone du myelome experience. J Clin Oncol. 2013;31(22):2806-9. 8. Thieblemont C, Grossoeuvre A, Houot R, Broussais-Guillaumont F, Salles G, Traulle C, et al. NonHodgkin's lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome. Ann Oncol. 2008;19(4):774-9. 9. Piccirillo JF, Vlahiotis A, Barrett LB, Flood KL, Spitznagel EL, Steyerberg EW. The changing prevalence of comorbidity across the age spectrum. Crit Rev Oncol Hematol. 2008;67(2):124-32. 10. Handforth C, Clegg A, Young C, Simpkins S, Seymour MT, Selby PJ, et al. The prevalence and outcomes of frailty in older cancer patients: a systematic review. Ann Oncol. 2015;26(6):1091-101. 11. Hasselblom S, Ridell B, Nilsson-Ehle H, Andersson PO. The impact of gender, age and patient selection on prognosis and outcome in diffuse large B-cell lymphoma - a population-based study. Leuk Lymphoma. 2007;48(4):736-45. 12. Sateren WB, Trimble EL, Abrams J, Brawley O, Breen N, Ford L, et al. How Sociodemographics, Presence of Oncology Specialists, and Hospital Cancer Programs Af fect Accrual to Cancer Treatment Trials. J Clin Oncol. 2002;20(8):2109-17. 13. Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105(11):168492. 14. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119(1):34-43. 15. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443-59. 16. Maksimovic N, Zaric M, Gazibara T, Trajkovic G, Maric G, Miljus D, et al. Incidence and Mortality Patterns of Acute Myeloid Leukemia in Belgrade, Serbia(1999–2013). Medicina(Kaunas). 2018;54(1):5. 17. Ocias LF, Larsen TS, Vestergaard H, Friis LS, Abildgaard N, Frederiksen H. Trends in hematological cancer in the elderly in Denmark, 1980–2012. Acta Oncol. 2016;55(suppl 1):98-107.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

18. Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116(19):3724-34. 19. Smith A, Roman E, Howell D, Jones R, Patmore R, Jack A. The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research. Br J Haematol. 2010;148(5):739-53. 20. Pulte D, Jansen L, Castro FA, Brenner H. Changes in the survival of older patients with hematologic malignancies in the early 21st century. Cancer. 2016;122(13):2031-40. 21. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41(2):6776. 22. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278-85. 23. Crombag MR, Joerger M, Thurlimann B, Schellens JH, Beijnen JH, Huitema AD. Pharmacokinetics of Selected Anticancer Drugs in Elderly Cancer Patients: Focus on Breast Cancer. Cancers (Basel). 2016;8(1). 24. Imbruvica. 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/205552s026,210563s002lbl.pdf. 25. Calvo E, Walko C, Dees EC, Valenzuela B. Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies. Am Soc Clin Oncol Educ Book. 2016(36):e175-e84. 26. John V, Mashru S, Lichtman SM. Pharmacological Factors Influencing Anticancer Drug Selection in the Elderly. Drugs Aging. 2003;20(10):737-59. 27. Van Spronsen DJ, Janssen-Heijnen ML, Lemmens VE, Peters WG, Coebergh JW. Independent prognostic effect of co-morbidity in lymphoma patients: results of the population-based Eindhoven Cancer Registry. Eur J Cancer. 2005;41(7):1051-7. 28. Juliusson G. Older patients with acute myeloid leukemia benefit from intensive chemotherapy: an update from the Swedish Acute Leukemia Registry. Clin Lymphoma myeloma Leuk. 2011;11 Suppl 1:S54-9. 29. Sokol KC, Knudsen JF, Li MM. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther. 2007;32(2):169-75. 30. Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-87. 31. Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Ellis LR, et al. The Feasibility of Inpatient Geriatric Assessment for Older Adults Receiving Induction Chemotherapy for Acute Myelogenous Leukemia. J. Am. Geriatr. Soc. 2011;59(10):1837-46. 32. Koll TT, Rosko AE. Frailty in Hematologic Malignancy. Curr Hematol Malig Rep. 2018;13(3):14354. 33. Abel GA, Klepin HD. Frailty and the management of hematologic malignancies. Blood. 2018;131(5):515-24. 34. Palumbo A, Bringhen S, Mateos M-V, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068-74. 35. Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Pardee TS, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121(21):4287-94. 36. Goede V, Bahlo J, Chataline V, Eichhorst B, Dürig J, Stilgenbauer S, et al. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: Results of the CLL9 trial of the German CLL study group. Leuk Lymphoma.. 2016;57(4):789-96.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

37. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. 1997;89(9):3323-9. 38. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481-5. 39. Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood. 2010;116(13):2224-8. 40. Engert A, Ballova V, Haverkamp H, Pfistner B, Josting A, Duhmke E, et al. Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol. 2005;23(22):5052-60. 41. Evens AM, Helenowski I, Ramsdale E, Nabhan C, Karmali R, Hanson B, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692-5. 42. Klapper W, Kreuz M, Kohler CW, Burkhardt B, Szczepanowski M, Salaverria I, et al. Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood. 2012;119(8):1882-7. 43. Patient's age and treatment for haematological malignancy: a report from the Haematological Malignancy Research Network (HMRN) 2014. Available from: https://www.hmrn.org/publications/reports. 44. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population based study. Haematologica. 2012;97(12):1916-24. 45. Lowenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989;7(9):1268-74. 46. Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The Outcomes and Costs of Acute Myeloid Leukemia Among the Elderly. Arch Intern Med. 2002;162(14):1597-603. 47. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015;94(7):1127-38. 48. Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider RS, Friedman MA. Representation of older patients in cancer treatment trials. Cancer. 1994;74(7 Suppl):2208-14. 49. Hutchins LF, Unger JM, Crowley JJ, Coltman CA, Jr., Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341(27):2061-7. 50. Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21(7):1383-9. 51. Yee KW, Pater JL, Pho L, Zee B, Siu LL. Enrollment of older patients in cancer treatment trials in Canada: why is age a barrier? J Clin Oncol. 2003;21(8):1618-23. 52. Dinmohamed AG, Visser O, van Norden Y, Blijlevens NM, Cornelissen JJ, Huls GA, et al. Treatment, trial participation and survival in adult acute myeloid leukemia: a population-based study in the Netherlands, 1989-2012. Leukemia. 2016;30(1):24-31. 53. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22(22):4626-31.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

54. Yonemori K, Hirakawa A, Komiyama N, Kouno T, Ando M, Fujiwara Y, et al. Participation of elderly patients in registration trials for oncology drug applications in Japan. Ann Oncol. 2010;21(10):2112-8. 55. Hori A, Shibata T, Kami M, Kusumi E, Narimatsu H, Kishi Y, et al. Age disparity between a cancer population and participants in clinical trials submitted as a new drug application of anticancer drugs in Japan. Cancer. 2007;109(12):2541-6. 56. Kanapuru B, Singh H, Myers A, Beaver JA, Kwitkowski VE, Farrell AT, et al. Enrollment of Older Adults in Clinical Trials Evaluating Patients with Hematologic Malignancies - the Food and Drug Administration (FDA) Experience. Blood. 2017;130(Suppl 1):861-. 57. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-64. 58. Cherubini A, Pierri F, Gasperini B, Zengarini E, Cerenzia A, Bonifacio E, et al. Are ongoing trials on hematologic malignancies still excluding older subjects? Haematologica. 2013;98(7):997-1000. 59. Dechartres A, Chevret S, Lambert J, Calvo F, Levy V. Inclusion of patients with acute leukemia in clinical trials: a prospective multicenter survey of 1066 cases. Ann Oncol. 2011;22(1):224-33. 60. Hamaker ME, Stauder R, van Munster BC. Exclusion of older patients from ongoing clinical trials for hematological malignancies: an evaluation of the National Institutes of Health Clinical Trial Registry. Oncologist. 2014;19(10):1069-75. 61. Bellera C, Praud D, Petit-Moneger A, McKelvie-Sebileau P, Soubeyran P, Mathoulin-Pelissier S. Barriers to inclusion of older adults in randomised controlled clinical trials on Non -Hodgkin's lymphoma: a systematic review. Cancer Treat Rev. 2013;39(7):812-7. 62. Srikanthan A, Vera-Badillo F, Ethier J, Goldstein R, Templeton AJ, Ocana A, et al. Evolution in the eligibility criteria of randomized controlled trials for systemic cancer therapies. Cancer Treat Rev. 2016;43:67-73. 63. Jin S, Pazdur R, Sridhara R. Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of Investigational New Drug Applications in 2015. J Clin Oncol. 2017;35(33):3745-52. 64. Kim ES, Bruinooge SS, Roberts S, Ison G, Lin NU, Gore L, et al. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-44. 65. Statler A, Radivoyevitch T, Siebenaller C, Gerds AT, Kalaycio M, Kodish E, et al. The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies. Leukemia. 2017;31(8):1808-15. 66. Shah JJ, Abonour R, Gasparetto C, Hardin JW, Toomey K, Narang M, et al. Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes. Clin Lymphoma Myeloma Leuk. 2017;17(9):575-83 e2. 67. Janssen-Heijnen ML, van Spronsen DJ, Lemmens VE, Houterman S, Verheij KD, Coebergh JW. A population-based study of severity of comorbidity among patients with non-Hodgkin's lymphoma: prognostic impact independent of International Prognostic Index. Br J Haematol. 2005;129(5):597-606. 68. Lee KW, Kim DY, Yun T, Kim DW, Kim TY, Yoon SS, et al. Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage. Cancer. 2003;98(12):2651-6. 69. Peters FP, Lalisang RI, Fickers MM, Erdkamp FL, Wils JA, Houben SG, et al. Treatment of elderly patients with intermediate- and high-grade non-Hodgkin's lymphoma: a retrospective population-based study. Ann Hematol. 2001;80(3):155-9. 70. Hamaker ME, Prins MC, Stauder R. The relevance of a geriatric assessment for elderly patients with a haematological malignancy--a systematic review. Leukemia research. 2014;38(3):275-83. 71. Glasdegib Prescribing Information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

72. Venclexta Prescribing Information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s011s014s015lbl.pdf . 73. George SL. Reducing patient eligibility criteria in cancer clinical trials. J Clin Oncol. 1996;14(4):1364-70. 74. Tournoux C, Katsahian S, Chevret S, Levy V. Factors influencing inclusion of patients with malignancies in clinical trials. Cancer. 2006;106(2):258-70. 75. Mengis C, Aebi S, Tobler A, Dähler W, Fey MF. Assessment of Differences in Patient Populations Selected for or Excluded From Participation in Clinical Phase III Acute Myelogenous Leukemia Trials. J Clin Oncol. 2003;21(21):3933-9. 76. Lemieux J, Amireault C, Camden S, Poulin J. Evaluation of factors associated with recruitment in hematological clinical trials: a retrospective cohort study. Hematology. 2010;15(6):373-7. 77. Unger JM, Vaidya R, Hershman DL, Minasian LM, Fleury ME. Systematic Review and MetaAnalysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation. J. Natl. Cancer Inst.. 2019;111(3):245-55. 78. Chouliara Z, Miller M, Stott D, Molassiotis A, Twelves C, Kearney N. Older people with cancer: perceptions and feelings about information, decision-making and treatment—a pilot study. Eur J Oncol Nurs. 2004;8(3):257-61. 79. Jenkins V, Farewell D, Batt L, Maughan T, Branston L, Langridge C, et al. The attitudes of 1066 patients with cancer towards participation in randomised clinical trials. Br J Cancer. 2010;103(12):18017. 80. Gross CP, Herrin J, Wong N, Krumholz HM. Enrolling older persons in cancer trials: the effect of sociodemographic, protocol, and recruitment center characteristics. J Clin Oncol. 2005;23(21):4755-63. 81. Marton A, Kezouh A, Petrogiannis-Haliotis T, Assouline S. Barriers to enrollment of patients with recurrent diffuse large B-cell lymphoma onto clinical trials. Leuk Lymphoma. 2015;56(9):2747-9. 82. Lara PN, Jr., Higdon R, Lim N, Kwan K, Tanaka M, Lau DH, et al. Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment. J Clin Oncol. 2001;19(6):172833. 83. Unger JM, Gralow JR, Albain KS, Ramsey SD, Hershman DL. Patie nt Income Level and Cancer Clinical Trial Participation: A Prospective Survey Study. JAMA Oncol. 2016;2(1):137-9. 84. Freedman RA, Dockter TJ, Lafky JM, Hurria A, Muss HJ, Cohen HJ, et al. Promoting Accrual of Older Patients with Cancer to Clinical Trials: An Alliance for Clinical Trials in Oncology Member Survey (A171602). Oncologist. 2018;23(9):1016-23. 85. Javid SH, Unger JM, Gralow JR, Moinpour CM, Wozniak AJ, Goodwin JW, et al. A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316). Oncologist. 2012;17(9):1180-90. 86. Benson AB, 3rd, Pregler JP, Bean JA, Rademaker AW, Eshler B, Anderson K. Oncologists' reluctance to accrue patients onto clinical trials: an Illinois Cancer Center study. J Clin Oncol. 1991;9(11):2067-75. 87. Hjorth M, Holmberg E, Rodjer S, Taube A, Westin J. Physicians' attitudes toward clinical trials and their relationship to patient accrual in a Nordic multicenter study on myeloma. Control Clin Trials. 1996;17(5):372-86. 88. Delivering High-Quality Cancer Care Charting a New Course for a System in Crisis. Editors: Laura Levit EB, Sharyl Nass, and Patricia A. Ganz. Authors: Committee on Improving the Quality of Cancer Care: Addressing the Challenges of an Aging Population; Board on Health Care Services; Institute of Medicine., editor. Washington (DC): National Academies Press (US); Dec 27 2013. 89. Hurria A, Levit LA, Dale W, Mohile SG, Muss HB, Fehrenbacher L, et al. Improving the Evidence Base for Treating Older Adults With Cancer: American Society of Clinical Oncology Statement. J Clin Oncol. 2015;33(32):3826-33.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

90. Dale W, Mohile SG, Eldadah BA, Trimble EL, Schilsky RL, Cohen HJ, et al. Biological, clinical, and psychosocial correlates at the interface of cancer and aging research. J Natl Cancer Inst. 2012;104(8):581-9. 91. Hurria A, Dale W, Mooney M, Rowland JH, Ballman KV, Cohen HJ, et al. Designing Therapeutic Clinical Trials for Older and Frail Adults With Cancer: U13 Conference Recommendations. J Clin Oncol. 2014;32(24):2587-94. 92. Mohile SG, Hurria A, Cohen HJ, Rowland JH, Leach CR, Arora NK, et al. Improving the quality of survivorship for older adults with cancer. Cancer. 2016;122(16):2459-568. 93. Report of the National Cancer Institute Clinical Trials Program Review Group August 26, 1997. Available from: https://deainfo.nci.nih.gov/advisory/bsa/bsa_program/bsactprgmin.pdf. 94. Lichtman SM, Harvey RD, Damiette Smit MA, Rahman A, Thompson MA, Roach N, et al. Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol. 2017;35(33):3753-9. 95. Lin NU, Prowell T, Tan AR, Kozak M, Rosen O, Amiri-Kordestani L, et al. Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol. 2017;35(33):3760-73. 96. Public workshop- Evaluating inclusion and exclusion criteria in clinical trials April 16, 2018. Available from: https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentst otheFDCAct/FDARA/UCM613054.pdf. 97. Singh H, Hurria A, Klepin HD. Progress Through Collaboration: An ASCO and U.S. Food and Drug Administration Workshop to Improve the Evidence Base for Treating Older Adults With Cancer. Am Soc Clin Oncol Educ Book. 2018(38):392-9. 98. Guideline for the Study of Drugs Likely to Be Used in the Elderly November 1989. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm07 2048.pdf. 99. Guidance for Industry: E7 Studies in Support of Special Populations: Geriatrics Questions and Answers February 2012. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM18 9544.pdf. 100. Guidance for Industry: Cancer Clinical Trial Eligibility Criteria: Patietns with Organ Dysfunction or Prior or Concurrent Malignancies 2019. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM63 3137.pdf 101. Guidance for Industry Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs 2019. Available from: https://www.fda.gov/media/127712/download. 102. FDASIA Section 907: Inclusion of Demographic Subgroups in Clinical Trials. Available from: https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/ FDASIA/ucm389100.htm. 103. Drug Trials Snapshots. Available from: https://www.fda.gov/drugs/informationondrugs/ucm412998.htm. 104. Patient-Focused Drug Development: Collecting Comprehensive and Representative Input Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders June 2018. Available from:

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

of

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM61 0442.pdf. 105. Jakafi: FDA; 2011. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf.

Journal Pre-proof Table 1. Proportion of Older Adults in Trials of Hematologic Malignancies Compared to Proportion of Older Patients with Cancer.

Years

Trial Population≥75 years %/ Cancer Population ≥75 years (%)

All¥

25/63

13/47^

SWOG 1993-1996

NR

930

Myeloma

25/70

NR

SEER 1992-1994

NR

1380

Lymphoma

14/16

NR

NR

1127

27/63

NR

69

4,174

All

22/58

NR

Myeloma

65/~69

NR

lP 119

ro

9#

169

Lymphoma

2/~45

NR

73

Leukemia

41/~65

NR

>500

23,000

All

NR

NR

Leukemia

9.6/55.6

495

59,300

All

32/61

NR

38

NR

Leukemia

Phase II~20/~60 Phase III~58/~60

NR

Jo

NCISponsored cooperative group trials 1992

Leukemia

ur

Statistics Canada 1993-1996

na

Yee et al

of

16,396

NCIC CTG 1993-1996

Trimble et al*

Trial Population≥65 years %/ Cancer Population ≥65 years (%)

164

-p

Hutchins et al

Number Number of Trials of evaluated patients Malignancy in in Trials Database (n) (n)

re

Publication

Study Database/ Population Database

Males-39.0/72.4 Males-11.0/33.5 Females-25.9/56.5 Females-5.0/28.6

2.3/28.2

SEER 1990

Lewis et al

NCISponsored cooperative group trials 1997-2000 SEER 1997

Early Stage -4 Late Stage-13

Phase II ~35/~50 Phase III ~40/~50 NR

Lymphoma

NR Early Stage 56/48 Late Stage 44/51

Journal Pre-proof

Myeloma

Phase II ~68/70 Phase III ~30/~70

NR

55

28,766

All

36/60

9/31

11

NR

Leukemia

~20/~55

NR

2

NR

Lymphoma

~45/~70

NR

26

NR

All

35/66

NR

1

NR

Lymphoma

1

NR

Myeloma

Yonemori et al.

Japan# Registration trials Japanese cancer population

ro

SEER 1995-1999

of

NR

-p

Talarico et al

FDA registration trials 1995-2002

11

0/63

NR

46/78

NR

Jo

ur

na

lP

re

SWOG -South West Oncology Group; NCIC CTG National Cancer Institute of Canada Clinical Trials Group; NR: Not reported ¥ Includes both solid tumor and hematologic malignancies ~Approximate estimate based on representation of data in figures *Data presented for only male patients with leukemia >65 years and >75 years ^Reported for patients ≥70 years; # Trials with available data related to proportion of patients 65 years and older. This report also included data from overseas registration trials; data not shown here.

Journal Pre-proof Table 2. Key Recommendations from FDA Guidance [98,99]. Patients in clinical trials should reflect population that will receive marketed drug Exclusions in early phase trials may not be necessarily maintained in phase III trials Arbitrary exclusions based on advanced age alone or presence of any concomitant illness or medication should be avoided without a good basis (influence safety or interpretation of study results)

of

Older adults preferably included in same trials as younger patient to allow direct comparisons and detect potential differences in treatment effects

ro

Safety, efficacy and dose response assessments by age in individual studies and

-p

integrated analysis should be evaluated

re

Pharmacokinetic analysis to evaluate effects of age associated conditions like renal or hepatic impairment and age-related differences not explained by the above factors

lP

Geriatric patients are arbitrarily defined as patients 65 years and older, important to

na

enroll patients in the age range 75 and above

Sufficient representation of older adult subgroups to permit comparison of response to

ur

younger patients

Jo

Representation of older adults in clinical trials should consider prevalence of the disease to be treated in the different age groups age or usage for other drugs of the same class or same indication by age

If applicable, marketing applications should include safety and efficacy data for various age groups (for example <65, 65-74, 75-84, and > 85) Design a study with inclusion and exclusion criteria to allow for inclusion of patients with comorbidities and concomitant therapies which are often noted in older patients

Journal Pre-proof Table 3. Key Recommendations from Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies Guidance for Industry [100]. Renal Function Recommendations Renal function eligibility criteria based on widely and clinically accepted equation that estimates glomerular filtration rate rather than absolute serum creatinine levels Justify renal function eligibility criteria based on available data and stage of product development

of

Include patients with renal impairment if available data indicate no increase in risk or steps to mitigate risks can be undertaken

ro

Address need and timing for studies to evaluate effect of dialysis and need for dose adjustment

-p

Cardiac function recommendations

re

Exclude patients with clinically significant cardiac failure particularly in early phase studies

lP

Include patients with cardiovascular dysfunction if totality of data suggest inclusion does not present an unreasonable risk

na

Investigator assessment of cardiac failure risk based on validated clinical classification system

ur

Baseline QTc prolongation evaluation in early phase studies developed in coordination with FDA If potential for QTc prolongation reasonable to include minimum baseline QTc interval

Jo

Reevaluate QTc criteria in late phase trials if early phase studies do not indicate concern for QTc prolongation Hepatic function recommendations Include patients with mild or moderate hepatic impairment if totality of data suggest inclusion does not present an unreasonable risk Criteria for Gilbert’s syndrome or stable chronic hemolytic anemia should be defined in the protocol Prior or concurrent malignancy Include patients if natural history of cancer or treatment does not impact safety or efficacy assessment of the study drug

-p

ro

of

Journal Pre-proof

re

120

110

lP

100

na

80 70

50 40 30 20 10

ur

60

Jo

RATE PER 100,000

90

0

AGE GROUP

AML

CML

CLL

NHL

Myeloma

Figure 1A. SEER Incidence Rates by Age at Diagnosis, SEER 18 2011-2015, All Races, Both Sexes.

Journal Pre-proof

8

RATE PER 100,000

7 6

5 4 3

2

of

1

AGE GROUP

ALL

-p

HL

ro

0

Jo

ur

na

lP

re

Figure 1B. SEER Incidence Rates by Age at Diagnosis, SEER 18 2011-2015, All races, Both Sexes.

Journal Pre-proof

10.5

1.5 4.2 6.6

9.5

12.6

90 22.6

29.8

13.9

29.6 17.9 16.9

21.3

5.3 6 4.9

0

AML <20

13.5

22.4

9.1 1.6 0.3

12.2

7.7 2.1

CL L 20-34

23.2

12

8.6

ro

9.5

31.2

55.4

CM L

ALL

35-44

45-54

HL

55-64

re

10

25.6

24.3

30 20

23.7

13

10.4

21.4

50 40

21.1

6.2

70 60

11.8

7.2

24.5

9

9.3

8.5

19.3

9.5

of

80

2.3 6.3

-p

100

5.3 3.6 1.7

10.9 2.8 0.5

N HL MYE L O MA 65-74

75-84

>84

Jo

ur

na

lP

Figure 2. Percent New Cases by Age Group (SEER 18 2011-2015, All Races, Both Sexes).