Hematological cancers, a group of cancer subtypes that include blood- and lymph-related disorders, account for 11% of all cancer diagnoses in the United States [1], with an estimated 1.9 million patients with hematological cancer currently living in the United States [1]. New noncurative therapies have led to improved survival for many hematological cancers; however, these maintenance medicines leave patients in a state of chronic disease. Approximately 60% of chronic hematological cancers, which include chronic leukemias (chronic lymphocytic and chronic myelogenous leukemia), low-grade lymphomas (follicular lymphomas), myeloma, myelodysplastic syndrome, and myeloproliferative neoplasms (MPNs), are incurable and typically follow unpredictable remitting-relapsing pathways associated with varying needs for treatment, which may be distressing for patients [2]; thus, these patients have distinct needs from those of patients with solid tumors (eg, breast cancer) [3]. Patients with chronic hematological cancers experience ongoing disease-induced symptoms that are frequently not resolved by medical therapy and chronic maintenance therapy-associated toxicities. This chronic symptom burden (eg, sleep disturbance, inflammation, fatigue, and emotional distress) persists into survivorship and re-emerges over time, despite the best available pharmacological therapy [1].

In particular, sleep disturbance (eg, difficulty falling asleep, difficulty staying asleep, nonrestorative sleep, or insomnia disorder) [4] is highly prevalent among patients with chronic hematological cancer [5]. Across studies, 50% to 80% of patients with hematological cancer have reported sleep disturbance [6-8]. Findings for the treatment of sleep disturbance in other highly studied cancer populations, such as breast cancer, may not be generalizable to patients with chronic hematological cancer, given their unique needs and disease course [9,10]. There is a pressing need for evidence-based, accessible treatments to improve sleep specifically in patients with chronic hematological cancers.

In addition, in patients with chronic hematological cancer, sleep disturbance is a predictor of increased inflammatory cytokine levels [10,11]; increased fatigue [10]; and poorer emotional functioning or emotional distress [10], including depressive symptoms [10]. In both noncancer and solid tumor cancer populations, sleep disturbance increases inflammation through persistent activation of the hypothalamic-pituitary-adrenal axis, which can, in turn, induce glucocorticoid resistance in immune cells, ultimately leading to a state of chronically elevated proinflammatory cytokines [12]. Sleep disturbance has also been shown to induce fatigue [13,14] and emotional distress [15-17]. The joint occurrence of sleep disturbance, fatigue, and emotional distress is referred to as symptom clustering [18] or grouping of interrelated symptoms. Such clusters have been shown to have a negative impact on patient survival [14,19]. These factors are also known to interact in complex ways, potentially leading to negative feedback loops that further affect symptom clustering (eg, as inflammation increases, further decrements in sleep and fatigue may be observed) [20].

Medications are the most commonly prescribed treatment for patients with cancer experiencing sleep disturbances; however, to date, there is insufficient evidence to conclude that they are truly effective, particularly when considering long-term treatment of sleep problems [4,21]. In addition, medication may exacerbate symptoms associated with chronic hematological cancer, such as increased severity of insomnia, fatigue, and pain [22]. Potential deleterious side effects, along with the poor long-term success of pharmacological treatment for managing sleep disturbance, may outweigh any potential effectiveness for improving sleep and related quality of life in patients with chronic hematological cancer, indicating a need for alternative, safe, and effective sleep management strategies.

Nonpharmacologic behavioral interventions are promising strategies for treating sleep disturbance because of their (1) limited side effects, (2) targeting of specific psychological and behavioral factors that interfere with sleep, and (3) potential for long-lasting effects [23]. Currently, cognitive behavioral therapy for insomnia (CBT-I) is the most widely available, evidence-based, nonpharmacological treatment strategy for managing sleep disturbances in patients with and survivors of cancer [24]. However, CBT-I is intensive and time consuming for patients, requiring frequent in-person meetings with therapists and physicians at sites or clinics [21]. Remote delivery of CBT-I may be an alternative approach; however, studies assessing remotely delivered CBT-I have not been conducted for patients with cancer [21]. Even app-based CBT-I requires considerable effort and time to be effective [21]. Specifically, cognitive behavioral therapy apps require both clinician involvement and support, along with high adherence on the patient’s side, to be effective [25]. Patients with chronic hematological cancer need less burdensome intervention strategies for long-term sleep management. Currently, patients with chronic hematological cancer have limited options for easily accessible, evidence-based treatments for sleep disturbance, exacerbating the diminished quality of life and resulting in poorer cancer outcomes.

Meditation is a sleep disturbance treatment strategy recommended by the American Cancer Society and the National Center for Complementary and Integrative Health. Mindfulness meditation is the practice of moment-to-moment awareness, in which a person purposefully focuses on the present without judgment [26]. Several reviews and meta-analyses have demonstrated the positive effects of mindfulness-based interventions for general sleep complaints and sleep parameters associated with sleep quality (eg, total sleep time, sleep efficiency, and sleep onset latency) [27-29], yielding moderate effect sizes comparable with those of standard of care treatments for insomnia [28]. Individual studies have also demonstrated effects on specific sleep disorders, including insomnia [30], narcolepsy [31], restless leg syndrome [32], and sleep apnea [33]. Ong et al [34] suggested that meditation promotes balanced appraisals, cognitive flexibility, equanimity, and recommitment to values, which can, in turn, allow sleep-related arousal to subside and normal sleep patterns to re-emerge. Shallcross et al [27] further posited that sleep disturbance involves five processes: (1) rumination, (2) primary arousal, (3) secondary arousal, (4) sleep monitoring and selective attention and effort, and (5) distorted perceptions. The core processes involved in mindfulness (ie, experiential awareness, attentional control, and acceptance) have the potential to target each of the 5 processes contributing to sleep disturbance [27].

Meditation also has a dose-response relationship with reductions in inflammation for both those with solid tumors and those without cancer [35-37]. One review found that mindfulness-based interventions had no effect on cytokines in healthy populations but improved cytokine levels in patients with cancer [38]. Mindfulness-based interventions aid the recovery of the immune system, and the resulting immune changes show a shift from a carcinogenic cytokine profile to a more normalized profile. Meditation and other mindfulness-based practices have improved inflammatory biomarker levels common in patients with chronic hematological cancer (eg, tumor necrosis factor-α [TNF-α], interleukin [IL]–6 [IL-6], IL-8, and C-reactive protein [CRP]), as well as in populations such as patients with insomnia disorder, survivors of cancer, and older adults [39-42]. These specific cytokines and proteins are the most common inflammatory cytokines closely associated with chronic hematological cancer disease progression, symptoms, and sleep disturbances across all hematologic malignancy subtypes [11,43,44]. The calming effects of meditation on the autonomic nervous system and the hypothalamic-pituitary-adrenal axis may reduce proinflammatory gene expression and signaling via the downregulation of the proinflammatory transcription factor necrosis factor κβ pathway [35,45].

Meditation has previously demonstrated improvements in both sleep disturbance and fatigue among a subset of patients with chronic hematological cancer (MPN), with patients reporting that their reductions in fatigue were because of better sleep quality [46,47]. Several other studies have established the effects of mindfulness interventions in reducing fatigue in patients with cancer [48-50]. For example, Ikeuchi et al [51] found that mindfulness affected fatigue both directly and indirectly through anxiety, depression, pain, loneliness, and sleep disturbances. Randomized controlled trials (RCTs) have also shown that meditation reduces sleep disturbance by reducing emotional distress (eg, anxiety and depression) in patients with and survivors of cancer [52] and reducing sleep-interfering cognitive processes (eg, ruminating thoughts) [53,54]. Mindfulness meditation may reduce stress, worry, intrusive thoughts, and presleep arousal, which may, in turn, reduce sleep disturbance [55]. In particular, patients with chronic hematological cancer are more likely to experience such issues as their disease is never cured.

Although the Society for Integrative Oncology Clinical Practice Guidelines [56] suggests that meditation is a safe technique for decreasing the burden of a variety of cancer-related symptoms and comorbidities, few studies have investigated the effects of mindfulness meditation on sleep disturbance, specifically in patients with chronic hematological cancer [57]. In 2 recent RCTs with patients with leukemia, meditation interventions were delivered in person in hospital settings by trained clinicians [58,59], thereby limiting accessibility and use, especially in patients who were fatigued, had inflexible schedules, or had transportation difficulties [60]. Traditional in-person meditation programs for patients with cancer are lengthy and potentially burdensome (eg, 30- to 60-minute sessions on a single day of the week [58]), especially for patients with chronic hematological cancer and high chronic symptom burden [61]. Of note, meditation studies with patients with leukemia had short durations (only 5 weeks in length), were conducted at a specific time during treatment and in a clinical inpatient setting (eg, during chemotherapy treatment sessions [58] or in the hospital [59]), and did not measure sustained practice or effects outside of the clinic setting. Prior studies of meditation in limited cancer settings have supported extending and testing flexible and effective modes of delivering meditation to understudied groups with cancer.

Research further demonstrates that patients with chronic hematological cancer are interested in smartphone apps as a means of self-managing their health [38-40]. As of April 2020, there were approximately 55 mobile apps marketed to patients with or survivors of cancer available in the Google Play and Apple App stores, offering mostly educational content and information for caregivers. Of these, 4 included some form of meditation. No commercially available meditation apps for cancer populations have been rigorously evaluated for their feasibility, safety, or effectiveness [41,42]. A review identified only 2 meditation studies for patients with cancer delivered via mobile apps; both focused on breast cancer, and only 1 tested a consumer-based app [62]. In one of these studies, an adapted mindfulness-based stress reduction (MBSR) program was delivered via an iPad, resulting in significant improvements in psychological status and quality of life among MBSR participants compared with a usual care control group [63]. However, this study was conducted over 6weeks without any follow-up [63]. The other study assessed a consumer-based app, Headspace, and found an increased quality of life and mindfulness in Headspace participants compared with the control group but did not obtain app use data in most participants [64]. Meinlschmidt et al [65] suggested that there is more value in identifying and testing popular and currently available tools that have a committed user base and are likely to remain in use in the near future. To date, few interventions have tested the effects of consumer-based, commercially available meditation apps for sleep, and none have been tested to reduce sleep disturbances in chronic hematological cancer. A summary of key takeaways from current literature in this area is presented in Textbox 1.

Therefore, leveraging a unique academic-industry partnership, we propose a 20-week RCT (8-week intervention+12-week follow-up) to rigorously test the consumer-based app Calm to effectively deliver a meditation intervention to patients with chronic hematological cancer (N=276; 138 per group) as compared with a health education podcast control group. Calm was chosen for this study as our research team had rigorously tested the app among patients with chronic hematological cancer previously, and we have demonstrated its preliminary efficacy and preference among patients with chronic hematological cancer over another popular meditation app, Headspace [47]. This study aims to (1) test the efficacy of daily meditation (≥10 minutes per day) delivered via Calm compared with a health education podcast control group in improving the primary outcome of self-reported sleep disturbance, as well as secondary sleep outcomes, including sleep impairment and sleep efficiency; (2) test the efficacy of daily meditation (≥10 minutes per day) delivered via Calm compared with a health education podcast control group on inflammatory markers (TNF-α, IL-6, IL-8, and CRP), fatigue, and emotional distress (anxiety and depressive symptoms); and (3) explore free-living use during a 12-week follow-up period and sustained effects at 20 weeks from the baseline of Calm in patients with chronic hematological cancer.

All study procedures and materials were approved by the Biomedical Research Alliance of New York Institutional Review Board (study 21-136-955) and conducted in accordance with the Declaration of Helsinki. This study has been registered at ClinicalTrials.gov (NCT05294991). Written informed consent will be obtained from all participants.

This study is a double-blind RCT in which eligible and consenting study participants will be randomly assigned to one of two groups: (1) the daily Calm meditation intervention group or (2) health education podcast control group.

Patients with chronic hematological cancers will be nationally recruited using previously established organizational partners (eg, Leukemia and Lymphoma Society, MPN Research Foundation, Patient Empowerment Network, Banner Health, and Mays Cancer Center at UT Health San Antonio MD Anderson). Recruitment materials will be developed specifically for each organizational partner to advertise the study to potential participants via social media (eg, Facebook, Instagram, and Twitter), email listservs, website postings, and postings in clinics or waiting rooms. The study will be advertised as an app-based wellness study to blind study participants to the intended Calm intervention group.

Interested patients with chronic hematological cancer will be directed to complete a web-based eligibility screening questionnaire via REDCap (Research Electronic Data Capture; Vanderbilt University; see Textbox 2 for a detailed list of the eligibility criteria). Ineligible participants will be sent an email notifying them of their ineligibility status and providing resources for patients with cancer, which will include an educational sleep handout and a discount code for Calm. Eligible participants will be sent an email notifying them of their eligibility; asked to review a video-based overview of the study (including the informed consent); and sent a link to electronically sign the informed consent via REDCap, a secure web-based data collection and management platform. Participants will be offered the option of scheduling a call with a member of the research team to review any questions related to the study before providing their consent. Once consent is signed, participants will be (1) asked to complete the baseline questionnaire via REDCap, (2) blindly and randomly assigned to either the Calm intervention or health education podcast control arm, and (3) emailed the study materials (eg, app download instructions, blood draw instructions, and welcome email with important dates and study milestones). As part of the study instructions, all participants will be asked not to participate in any similar interventions, including other meditation apps, medications, or nonpharmacological sleep interventions during the study period. Participants will be blocked or stratified by biological sex and then randomly allocated (with a 1:1 allocation ratio) within the male-female strata to treatments using a pseudorandom number algorithm provided by the study statistician. Research personnel who assign participants to a group will not be the same as those who enroll participants or download and clean data. The group allocation status will be restricted so that statisticians and researchers will remain blind to treatment assignment.

After randomization, all participants will be offered an app download coaching and tutorial call with a study team member to review their assigned app, including a review of (1) the general app layout and basic functionalities (eg, look, feel, and types of content found on the app), (2) where to find content and how the content is organized, (3) how to view participation-tracking statistics, (4) how to set reminders to meditate or view podcasts, and (5) how to share participation statistics on social media. Following the call, the participants will receive an email containing a phone number for continued support using the app.

In addition, the participants will receive blood draw instructions. Participants will have a blood draw request placed to obtain a blood draw from their local Quest Diagnostics Patient Service Center and instructed on the time of day to receive their blood draw and the forms of identification they will need to obtain the blood draw. Participants will have access to a study team member’s phone number and email for further support while receiving a blood draw throughout the study.

Finally, participants will receive a mailed package containing (1) an Actiwatch Spectrum device; (2) instructions detailing the wear, care, and use of the device; and (3) instructions for shipping the device back to the research team at the study conclusion. The participants will not proceed with the intervention until the previous steps are fully completed.

Calm does not provide its users with a specific prescription for how often to use the app (frequency) or how long to use the app (dose); users self-select the frequency, dose, and timing of engagement, as well as which content and features to use. The Calm intervention participants will be asked to complete a minimum of 10 minutes per day of meditation via Calm, at any time of day for 8 weeks. During weeks 1 to 4, participants will be asked to complete the introductory 30-day program How to Meditate comprising 30 days of 10-minute daily meditation along with education about what mindfulness is, how to practice and achieve it with meditation, the seated or reclining positions to use for meditation, and how to monitor and guide their breathing. During weeks 5 to 8, participants will be asked to complete one daily meditation that may include the Daily Calm, a different 10-minute mindfulness meditation each day, or a meditation from various series of meditations (eg, loving-kindness and 7 days of managing stress). Participants will have complete autonomy over choosing the meditation, which includes options for at least 10 minutes (meditation periods are tracked). After completing their daily meditation, participants will also be able to use the app content more broadly (ie, nonmeditative content, including Sleep Stories and Daily Move) based on their preference.

Calm meditation focuses on mindfulness components [66], breathing techniques, and body scans, all of which are consistent with core mindfulness practices, such as MBSR (nonjudgmental moment-to-moment awareness) [67] and one of Vipassana’s principles—objective observation of physical sensations in the body [68]. As an ideal dose for mindfulness meditation interventions has not been established because of considerable variability in intervention prescription [69], the 10-minute daily dose was chosen, as Calm currently offers 10-minute meditations (daily and series meditations), which corresponds to how long users typically meditate using the app. Practical guides recommend that beginners start with short daily meditations lasting between 10 and 30 minutes per session [26,70]; thus, the intervention prescription will be a minimum of 10 minutes per day of meditation to be effective but not overly burdensome.

Participants will be allowed to choose the time of day when they meditate. Giving participants autonomy over choosing the time of day for meditation mirrors the way in which Calm’s paying subscribers use the app, thus yielding benefits (eg, ecological validity and participant satisfaction) that likely outweigh those of imposing strict controls over the timing of use, which could lead to lower adherence (eg, missed or truncated practice). Participation (meditations completed, time of day, length of time, and nonmeditative content used) will be tracked using the Calm app throughout the study and addressed in sensitivity analyses.

After completion of the 8-week study intervention period, the Calm intervention participants will no longer have to complete daily meditations but will continue to have access to the app for 12 additional weeks during the follow-up period. Participation in the Calm app will continue to be tracked during this time.

Similar to the Calm intervention group, podcast group participants will listen to a minimum of 10 minutes per day of a health education podcast delivered via a mobile app for 8 weeks (Tables 1 and 2). A library of health education podcasts will be available on the app, with carefully chosen content that excludes any recommendations for sleep, meditation, or mindfulness-like principles or practice. Participants will be able to select the podcast based on title, time, or both in an effort to mirror the delivery of meditations in the Calm intervention group. Podcast group participants will also be encouraged to use other components of the podcast. Participation (podcasts completed, time of day, length of time, and components used) will be tracked on the app throughout the study period. After completion of the 8-week sham intervention period, the podcast group participants will no longer be asked to listen to daily podcasts but will continue to have access to the app for 12 additional weeks during the follow-up period. Participation in the podcast app will still be tracked during this period. Upon completion of the entire 20-week study period, podcast group participants will be given a discount code for 6 months of free access to the Calm app.

We will use self-determination theory (SDT) and SDT-based strategies to guide our protocol and promote adherence [71]. The SDT postulates that the initiation and maintenance of behavior is influenced by three basic needs:(1) competence, or the need to produce desired outcomes and to experience mastery; (2) autonomy, or the need to feel ownership of one’s behavior; and (3) relatedness, or the need to feel connected to others [72]. Participants will be encouraged to use the features built into the Calm intervention or podcast, which are designed to help maintain engagement and adherence in their assigned app. All these features are consistent with practices that help individuals participate in health behaviors [71], and these features are identical in both apps. To promote autonomy, a feature of the Calm and podcast apps includes time spent meditating or listening to podcasts—participants can go to their Calm profile and they are automatically provided the total time they have spent meditating or listening (time from the first meditation or podcast to present), total sessions, and longest streak after each use. To promote competence, the Calm and podcast apps include a reminder that participants can set in the app that will send them a push notification to meditate or listen to a podcast at a set time each day. To promote relatedness, the final feature of the Calm and podcast apps includes Share Your Stats, which allows participants to share summaries of their meditation or podcast listening use with others via SMS text messages, emails, or social media (eg, Facebook, Pinterest, or Instagram).

In addition to the above app features, EZTexting (a commercial SMS text messaging–based platform) will be used to send a brief, automated phone call, email, or SMS text message (based on participant preference) at the beginning of the week to encourage continued participation, with the message and conversation grounded in the 3 tenets of SDT (ie, autonomy, competence, and relatedness). Participants who are not meditating or listening to the podcast episodes for at least 10 minutes per day or 70 minutes per week for >3 consecutive days will receive a midweek phone call, email, or text (based on participant preference) through EZTexting. Participants could opt out of these follow-up messages at any time during the intervention. Research staff will track adherence information throughout the study and determine whether the patterns of use are similar across arms. Furthermore, both the Calm intervention and podcast will automatically show the user their time spent in meditation or listening for the day, the total time since the start of the study, and the longest streak as a reinforcing self-management technique. Finally, the Calm intervention and podcast also include reminder tools in which participants can set reminders on their phones to participate [73]. All study participants will receive a monetary incentive for completion of the baseline (US $15), postintervention (US $25), and follow-up (US $35) assessments, including blood draws, for a total incentive opportunity of US $75 paid in one lump sum at the end of the study if all 3 outcome time points are completed.

The purpose of this study is to leverage an academic-industry partnership with the consumer-based app Calm to rigorously evaluate Calm for the effective delivery of a meditation intervention to patients with chronic hematological cancer via a 20-week RCT. Specifically, in this study, we aimed to (1) test the efficacy of daily meditation (≥10 minutes per day) delivered via Calm compared with a health education podcast control group on self-reported sleep disturbance, sleep impairment, and sleep efficiency; (2) test the efficacy of daily meditation (≥10 minutes per day) delivered via Calm compared with a health education podcast control group on inflammatory markers, fatigue, and emotional distress; and (3) explore the sustained effects at 20 weeks from the baseline of Calm in patients with chronic hematological cancer. This study will be the first RCT to determine the effects of a consumer-based mobile meditation app on sleep disturbances in patients with chronic hematological cancer. If our findings demonstrate a significant clinical impact on sleep disturbance in patients with chronic hematological cancer, we will have an inexpensive, easily accessible, nonpharmacological intervention that can readily be prescribed by cancer care providers for sleep disturbance in chronic hematological cancer. Our rigorous RCT will fill a knowledge and rigor gap regarding the delivery of smartphone-based meditation as an intervention for sleep and provide new data on sustained effects.

There is limited understanding of the effects of meditation on sleep-related outcomes in patients with cancer, with no research to date examining these outcomes in hematological cancers (1.9 million in the United States) [28,57]. Existing research using apps has focused on emotional measures or cancer-specific biological changes as outcomes but not sleep disturbance [90-94] in survivors of solid tumors with minimal residual disease or those with short survival times (eg, patients with metastatic solid tumors). The different and distinct long-term disease courses of patients with chronic hematological cancer and the associated maintenance therapy toxicities and symptoms warrant innovative interventions that support the self-management of symptoms [3]. Patients with chronic hematological cancer are often geographically dispersed, with substantial variability in their proximity to cancer centers because of the rarity of certain subtypes (eg, MPNs) [95], limiting opportunities for community-based local programs to help manage symptoms. Remote delivery of meditation via a mobile app will improve reach and scalability in this understudied population.

In addition, previous studies on meditation in cancer have focused primarily on White women with breast cancer [57]. This study presents an opportunity to study meditation in older adults, men, and minorities who present with chronic hematological cancer. Our prior successful recruitment strategies for patients with cancer will specifically recruit representative samples from these populations. Furthermore, we previously established that Calm is acceptable and appealing to a wide population group, which can expand the reach of traditional research interventions. For example, in a cross-sectional survey of Calm subscribers (N=12,151), 20% were male, 19% were people of color, and 15% were older adults (aged >65 years).

Prior studies using meditation to reduce sleep disturbance in patients with cancer did not have follow-up periods beyond 12 weeks [53]. In the 2 meditation-based interventions conducted in patients with chronic hematological cancer, both were delivered for a very short period (ie, 5 sessions of 1 hour per week). No product could be used continually and accessed beyond study completion [58,59]. As most evidence-based apps are developed within the context of research studies and are not sustained at the end of the study [96], the scalability and viability of the widespread distribution of mobile app–based interventions in these studies are not possible. As Calm is consumer based, the intervention never truly ends. Calm is available and can be used whenever a patient desires or feels it is needed (eg, when they feel overwhelmed, fatigued, anxious, or lying down to go to sleep). The patient can choose when and how frequently Calm is used, increasing the likelihood that patients will use Calm to alleviate sleep disturbance in the long term. This study can uniquely measure and explore time and dose effects and will advance the evidence for a consumer-based meditation app that patients with chronic hematological cancer can use for symptom self-management in the long term. This research will contribute to broader public health efforts by providing researchers and clinicians with an evidence-based commercial product to improve sleep in the long term in an underserved and understudied population with cancer and a high incidence of sleep disturbance.

If it is demonstrated that Calm is an efficacious intervention for patients with chronic hematological cancer, future work will aim to disseminate Calm as an evidence-based option for health care providers to recommend or prescribe to patients with chronic hematological cancer. Consideration will be made to apply for a NIH Small Business Innovation Research grant to help with the dissemination of Calm or to receive Food and Drug Administration approval for Calm as a nonpharmacological intervention for the treatment of sleep in patients with chronic hematological cancer.

In summary, this study will contribute to the mindfulness and cancer literature at large, with a unique focus on filling the much-needed gap by examining remote mindfulness-based interventions in patients with chronic hematological cancer.