High Hopes

Hematology patients are turning to cannabis for symptom relief, but should they?

As of October 2017, 28 states and the District of Columbia had legalized medical or recreational marijuana. However, the plant is still considered a “schedule I substance” under the Controlled Substance Act, which means it has a high potential for abuse; no accepted medical use; and falls into the same category as heroin, LSD, and ecstasy – at least according to the federal government.1 In 2016, responding to petitions asking for marijuana to be “rescheduled” for the benefit of scientific research, the Drug Enforcement Agency (DEA) doubled down on its insistence that cannabis and its compounds are recreational drugs, not medicine.2 At the same time, another federal agency, the U.S. Food and Drug Administration (FDA), approved two cannabis-derived products for a variety of indications.3,4

Despite the conflict between state and national laws and the confusion among federal agencies, many patients with cancer have embraced marijuana to help manage their cancer and cancer-related symptoms.

“Patients with hematologic malignancies often seek aggressive treatment, including transplants, nearly up until the end of life,” David Casarett, MD, chief of palliative care at Duke University in Durham, North Carolina, told ASH Clinical News. This can mean weeks and months of active treatment when they do not have access to hospice care, he explained. “For those patients, there is a particularly strong need for palliative care delivered alongside aggressive treatment; medical cannabis represents one option for palliative care.”

If patients are using marijuana medicinally, the onus is on their physicians to address their use. “As physicians, we need to have conversations about the use of medical marijuana with our patients,” noted Steven Pergam, MD, MPH, medical director of infection prevention at the Seattle Cancer Care Alliance in Washington, a state where medicinal and recreational marijuana use is legal. “Many physicians are skeptical about its benefits, and it’s true that there are few data on its risks and benefits, but if we don’t talk to our patients about it, they will talk with other people [who] may not be the best sources of information.”

As evidenced by the patchwork of marijuana legalization laws in the U.S., the acceptance of medical marijuana is still hazy. ASH Clinical News spoke with Drs. Casarett and Pergam and other health-care professionals and researchers about medical marijuana for patients with hematologic diseases, including patient and provider attitudes and the challenges of answering clinical questions about the therapy.

Cannabis: A Wacky Tobacky

According to the FDA, the term “medical marijuana” refers to using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illnesses.5 Although the FDA has not recognized or approved the botanical marijuana plant or any product containing it as a medicine, researchers have studied the medicinal value of cannabinoids (the chemicals in marijuana) and cannabinoid-based products.

Scientists have identified more than 525 constituents in the cannabis plant, including about 100 different cannabinoids.1 The most psychoactive cannabinoid is delta-9-tetrahydrocannabinol (THC), and the second most active component is cannabidiol (CBD). The cannabis plant has two main subspecies: Cannabis indica, which has the higher CBD content, and Cannabis sativa, which has the higher THC content.5

When a person ingests cannabis, the active ingredients attach to binding sites (cannabinoid receptor type 1 and type 2 [CB1R and CB2R]) throughout the body. CB1R sites are primarily located in the brain, but they also appear in the liver, thyroid, bones, peripheral nervous system, and testicles; CB2R sites are mostly found in immune cells, the spleen, and the gastrointestinal system, but they also appear in the brain and peripheral nervous system. The receptors have also been shown to play a role in regulating serotonin transporter activity.

Although the medical marijuana community has come up with creative ways to deliver the agent, the most common is through inhalation: Cannabis is smoked or vaporized, and the THC enters the bloodstream and quickly makes its way to the brain. However, the effects of inhaled marijuana generally fade just as quickly.

Cannabis can also be delivered in “edibles” – baked goods, candies, and other foods infused with cannabis extracts and tinctures. With ingested cannabis, THC absorption can take hours. Once it is absorbed, THC is processed in the liver, producing a substance that acts on the brain to alter mood or consciousness.6

“[Patients] need
… palliative care
delivered alongside
aggressive treatment;
medical cannabis
represents one option
for palliative care.”

David Casarett, MD

The Wonder Drug

The effects of cannabis’ psychoactive compounds make it an obvious candidate for managing the side effects of cancer treatment. “Cannabis is useful in combatting anorexia, chemotherapy-induced nausea and vomiting, pain, insomnia, and depression,” explained Donald Abrams, MD, chief of hematology/oncology at San Francisco General Hospital in California. “[It] might be less potent than other available anti-emetics, but for some patients, it is the only agent that works, and it is the only anti-emetic that also increases appetite.”

In a trial of patients with advanced cancer and impaired chemosensory perception, those who received THC capsules reported that they had enhanced chemosensory perception, better pre-meal appetite, and that food “tasted better.”7

A systematic review of cannabis-derived products indicated that cannabinoids were more effective than several anti-emetics; patients also preferred to use cannabinoids over traditional anti-emetics for future chemotherapy cycles.8 However, another review found that adverse events (AEs) were more intense and occurred more frequently in patients using cannabinoids versus traditional anti-emetics.9

The FDA has approved two cannabinoid-based drugs for the treatment of chemotherapy-related nausea and vomiting: dronabinol and nabilone.3,4 The active ingredient in each is a synthetic version of delta-9-THC, a cannabinoid naturally occurring in Cannabis sativa. Dronabinol is also approved for the treatment of anorexia-associated weight loss in patients with AIDS. The approval language states that dronabinol and nabilone be used to manage nausea and vomiting only after patients have tried conventional anti-emetic agents.

Researchers also have high hopes for cannabinoids’ palliative effects in other diseases, including sickle cell disease (SCD), characterized by chronic pain. In a study presented at the 2016 ASH Annual Meeting, Nene Kalu, MSW, a social worker at the Center for Sickle Cell Disease at Howard University in Washington, D.C., and colleagues assessed the prevalence of marijuana use and hydroxyurea use (the only FDA-approved therapy for SCD at the time of study) in 103 SCD patients.10 Patients completed questionnaires about their use of marijuana or hydroxyurea during steady states and during moderate to severe pain crises.

More than half of patients (56%) said they had used both drugs, whereas 44 percent said they had only used marijuana. Thirty percent stated they had used marijuana within the past 12 months to relieve symptoms associated with SCD, such as boosting appetite, improving sleep, elevating mood and concentration, relieving stress and anxiety, and alleviating pain. However, 80 percent of participants stated that marijuana was not as effective as hydroxyurea in managing their SCD-related pain.

For a closer look at an emerging indication for patients with hematologic malignancies, see the SIDEBAR.

High and Dry

To gather clinical data on cannabis’ therapeutic uses, researchers need to conduct more studies – a point the DEA agrees with – but the agency also firmly believes that cannabis has no medicinal value.

To expand research opportunities, though, the agency said it “will allow additional entities to apply to become registered with [the] DEA so that they may grow and distribute marijuana for FDA-authorized research.” The DEA will oversee the new growers and ensure that trials are “scientifically valid and well-controlled.”2

Because of the lack of long-term, randomized clinical trials of cannabis in patient populations, a full understanding of how and why natural cannabis works still eludes investigators. The restrictions have also hampered further development of synthetic cannabinoid-based products.

Given the federal government’s continued chokehold on cannabis use, “to do randomized, placebo-controlled clinical trials is very difficult,” Dr. Abrams said, adding that he served on the National Academies of Sciences, Engineering, and Medicine committee that issued a report on cannabis and cannabis-derived products in January 2017.11 “We outlined very clearly the barriers to doing research with cannabis,” he said, which include its schedule I classification; inadequate financial support; and limited access to the quantity, quality, and type of cannabis product necessary to address specific research questions on the health effects of cannabis use.

Both proponents of medical marijuana and regulators are worried about the quality of cannabis products and the potential for AEs with poor-quality cannabis. For example, Dr. Abrams explained, concerns about pulmonary aspergillosis may dampen patient and clinician enthusiasm for medical cannabis. The pulmonary infection is triggered by direct inhalation of fungal spores that can be present on cannabis plants. Heating cannabis buds may not be enough to sterilize them, potentially exposing those with compromised immune systems to the fungus. The age of the plant and the way it is stored during shipment can contribute to the presence of mold.12

For patients with acute myeloid leukemia who are immunocompromised and smoke, rates of acquiring aspergillus infection may be 12-times higher than those who don’t smoke. For those who smoke marijuana, aspergillus infection rates can be higher still.13 The incidence may decrease in today’s more-accepting legal environment; the way the plant is grown, stored, and transported has evolved as medical dispensaries have taken hold. “Cannabis gets infected with mold and fungus when people used the ‘old-school’ methods of cannabis coming in from Mexico on boats, being sprayed down and hidden under tarps,” Dr. Abrams suggested.

Reefer Madness

The research is sparse for hematology patients, who are either left out of studies or opt not to participate in them.

A study out of the Sheba Medical Center in Tel Aviv, where medical cannabis is legal, evaluated patterns of use among patients with cancer at a single institution. Of 17,000 cancer patients (excluding those with hematologic malignancies), the vast majority of cannabis users had metastatic disease, and they found the agent useful for improving pain, boosting general well-being, increasing appetite, and controlling nausea.15

Researchers at the Smilow Cancer Hospital at Yale in New Haven, Connecticut, a state where medical cannabis is legal, described their clinical experience with the agent. Among 108 patients with cancer who initiated medical marijuana under the supervision of a palliative-care specialist, the overwhelming majority had solid tumors, compared with hematologic malignancies (91% vs 9%). As with the Israeli study, most of the patients who used medical cannabis had late-stage disease and used the agent to manage pain and cachexia.16

Similarly, in a survey-based study of 926 cancer patients at their institute in Washington, Dr. Pergam and colleagues found that the largest group of respondents had an underlying solid tumor malignancy (66%), and the remaining one-third had a hematologic malignancy.17

The lack of representation in formal trials doesn’t mean that patients with hematologic malignancies are turning away from cannabis use. In Dr. Pergam’s group, 24 percent of patients reported using cannabis in the previous year, and 21 percent reported using it in the past month – primarily to treat physical and neuropsychiatric symptoms. Though active cannabis users were less likely to be hematopoietic cell transplant recipients in comparison with prior and never users, the underlying type of cancer ultimately did not influence rates of cannabis use.

Dr. Casarett noted anecdotally that the patients with blood cancer that he treats are not averse to cannabis use.

“I practice in a state in which medical cannabis is not legal, so I can’t make recommendations; however, many of my patients with cancer and other diagnoses use it,” he said. “In my experience, patients with hematologic malignancies seem to use medical cannabis more for anxiety, sleep, and nausea, compared [with] patients with solid tumors, for whom pain seems to be more prominent as an indication.”

“I was surprised by the low number of patients with hematologic malignancies in the study because we see a large number of those patients here, including many transplant patients,” Dr. Pergam explained. “But I think because of concerns about infection risk, patients with [hematologic malignancies] are either less interested or are talked out of using medical cannabis. Perhaps the messaging from their clinicians is different.”

“We need to talk
about this with
patients. … The risks
and benefits of
cannabis use can
be very different
according to the
patient’s situation.”

Steven Pergam, MD, MPH

Clinicians and the Cannabis Conundrum

For physicians, concerns about patients’ cannabis use boils down to two broad questions: What are the health risks associated with cannabis use, including potential adverse effects? Are patients using the agent without their health-care team’s knowledge, and, if so, why?

“There really are some benefits to medical marijuana,” Dr. Casarett said in a 2016 TEDMed Talk. “Those benefits may not be as huge or as stunning as some of the most avid proponents of medical marijuana would have us believe, but they are real.”18 However, “medical marijuana does have some risks. Those risks may not be as huge and as scary as some of the opponents of medical marijuana would have us believe, but they are real risks, nonetheless.”

In addition to the rare occurrences of Aspergillus respiratory infections, the risks associated with the inhalation include more frequent chronic bronchitis episodes, higher forced vital capacity, asthma development or exacerbation, and chronic pulmonary obstructive disease.11

In a meta-analysis of oral cannabinoids for anti-emesis, AEs associated with the therapy included paranoid delusions, hallucinations, dysphoria, and depression.7 The AEs were enough to convince some patients to leave studies, the authors noted.

The connections between cannabis and other AEs are more tenuous. There is limited or insufficient evidence to link the use of cannabis to a higher risk for the development of solid tumors or hematologic malignancies, such as AML and acute lymphocytic leukemia, or to an increased risk for cardiovascular disease or type 2 diabetes.11

Dr. Pergam emphasized that he would not recommend cannabis use for patients who are immunocompromised or have neutropenia. Also, obviously, “if someone has respiratory health issues, I wouldn’t recommend that they smoke it,” he noted.

Dr. Abrams pointed out that, to date, no studies have shown botanical-pharmaceutical interaction between cannabis and prescription medications in patients’ plasma concentrations. A pharmacokinetic study of 21 patients with chronic pain who were taking sustained-release opioids for pain management showed that, when patients also used vaporized cannabis, there was no significant effect on plasma levels of the opioid.19 There was also a suggestion of enhanced analgesia, meaning that combining the two drugs could allow for opioid dose reductions.

Findings from ongoing studies also should alleviate some concerns that cannabis use could reduce the effectiveness of established chemotherapy agents. In in vitro and animal models, pairing cannabis extracts with chemotherapy agents led to a synergism in reducing cell numbers, with no negative effect on anti-cancer function. Cell cultures from different solid tumors have been investigated with several antineoplastic agents – gemcitabine, paclitaxel, 5-fluorouracil, among others – and synergism in inducing cancer cell death was a common finding.20

Some Pot in Every Kitchen?

Although clinicians may want further evidence that cannabis does more good than harm, patients are generally on board with using cannabis for symptom management. In the cross-sectional, anonymous survey by Dr. Pergam’s group, 66 percent of the respondents said they had used cannabis at some point in their lives, and almost one-fourth considered themselves to be active cannabis users.

Most respondents also expressed a strong interest in learning about cannabis during treatment; 74 percent wanted information from their cancer-care providers, but less than 15 percent reported that they received such information.17

That is problematic, according to the experts. Even for physicians who practice in a state where marijuana has not been legalized, conversations about use, or interest, in cannabis is important. “We need to talk about this with patients. If we’re not asking questions about cannabis use, then we’re doing a disservice to them,” Dr. Pergam said. “Even though we don’t always know the best answer, having that discussion allows it to be a shared decision. The risks and benefits of cannabis use can be very different according to the patient’s situation.”

For example, Dr. Pergam said he would not recommend cannabis use for a patient about to undergo a bone marrow transplant, but it may be suitable for a patient with late-stage cancer who is looking for palliative relief. Again, he emphasized that if patients don’t ask their physicians about cannabis, they’ll get information elsewhere. “I’m a little more skeptical of where the other data come from,” he said.

Dr. Abrams agreed that he would hesitate to suggest cannabis use for certain patient populations, such as older patients with certain comorbidities, including cardiovascular disease. “Cannabis could raise or lower blood pressure, increase pulse, and put a strain on the heart,” he explained. “Or if it causes orthostatic hypertension, it could lead to falls, and that’s not good in older people. I’m also a bit more cautious recommending it for people who have had a prior negative experience with [recreational] cannabis.”

As public opinion about medical cannabis shifts, and as more legislative bodies accept cannabis for medicinal use, physicians can no longer hide behind the excuse of too-little evidence-based medicine to avoid the topic with their patients – or to advise patients against cannabis use altogether, Dr. Abrams said.

“As an integrative oncologist, I notice that the default mechanism for conventional oncologists is to tell patients to stop using all botanicals and supplements when their liver function tests are elevated,” he said. “More often than not, though, the chemotherapy is elevating liver function. But people have blinders on and are willing to blame everything on the botanicals.”

A more open discussion about cannabis use will also allow scientists to pinpoint possible drug interactions and more effectively manage patients’ treatment, Dr. Casarett stressed. “Potential interactions with other drugs is the most important reason why health-care providers need to be proactive in engaging their patients in discussions,” he wrote. “We can’t provide guidance and counseling if we don’t know whether – and why – our patients are using medical cannabis.”


References

  1. U.S. Drug Enforcement Administration. “DEA Drug Fact Sheet: Marijuana.” Accessed November 2, 2017, from https://www.dea.gov/druginfo/drug_data_sheets/Marijuana.pdf.
  2. U.S. Drug Enforcement Administration. “DEA Announces Actions Related to Marijuana and Industrial Hemp, August 11, 2016.” Accessed November 2, 2017, from https://www.dea.gov/divisions/hq/2016/hq081116.shtml.
  3. U.S. Food and Drug Administration. “Marinol prescribing information.” Accessed November 2, 2017, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205525s000lbl.pdf.
  4. U.S. Food and Drug Administration. “Cesamet prescribing information.” Accessed November 2, 2017, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018677s011lbl.pdf.
  5. U.S. Food and Drug Administration. “FDA and Marijuana: Questions and Answers.” Accessed November 2, 2017, from https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm.
  6. American Cancer Society. “Marijuana and Cancer.” Accessed November 2, 2017, from https://www.cancer.org/treatment/treatments-and-side-effects/complementary-and-alternative-medicine/marijuana-and-cancer.html.
  7. Brisbois TD, de Kock IH, Watanabe SM, et al. Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol. 2011;22:2086-93.
  8. Tramèr MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. Br Med J. 2001;323:16-21.
  9. Machado Rocha FC, Stéfano SC, De Cássia Haiek R, et al. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl). 2008;17:431-43.
  10. Kalu N, O’Neal PA, Nwokolo C, et al. The use of marijuana and hydroxyurea among sickle cell patients. Blood. 2016;128:5913.
  11. National Academies of Science, Engineering, and Medicine. “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research 2017.” Accessed November 2, 2017, from https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state.
  12. Gargani Y, Bishop P, Denning DW. Too many mouldy joints – marijuana and chronic pulmonary aspergillosis. Mediterr J Hematol Infect Dis. 2011;3:e2011005.
  13. Mukherjee S, Fu AZ, Mansour M, et al. Cigarette smoking significantly increases the risk of invasive fungal disease (IFD) in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Abstract #3595. Presented at the 2011 ASH Annual Meeting, December 12, 2011; San Diego, CA.14. Wallace JM, Lim R, Browdy BL, et al. Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease. Chest. 1998;114:131-7.
  14. Waissengrin B, Urban D, Leshem Y, et al. Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience. J Pain Symptom Manage. 2015;49:223-30.
  15. Daleo SJ, Davis M, Pham T, et al. Incorporating medical marijuana in clinical practice. J Clin Oncol. 2017;35:117.
  16. Pergam SA, Woodfield MC, Lee CM, et al. Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer. 2017 September 25. [Epub ahead of print]
  17. Casarett D. “A Doctor’s Case for Medical Marijuana – TEDMed 2016.” Accessed November 2, 2017, from https://www.ted.com/talks/david_casarett_a_doctor_s_case_for_medical_marijuana.
  18. Abrams DI, Couey P, Shade SB, et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Therap. 2011;90:844-51.
  19. 20. Ward SJ, McAllister SD, Kawamura R, et al. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014;171:636-45.

Graft-versus-host disease (GVHD) is a serious obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT), and cannabidiol (CBD) may decrease GVHD incidence and severity after alloHCT, according to results of a phase II study conducted in Israel.1

The investigators, led by Moshe Yeshurun, MD, of the Institute of Hematology at the Rabin Medical Center in Petah-Tikva, enrolled 48 patients, most of whom had acute leukemia or myelodysplastic syndromes. Of those, nearly three-fourths underwent a pre-alloHCT myeloablative conditioning regimen.

GVHD prophylaxis consisted of cyclosporine and short-course methotrexate, and all patients receiving a transplant from an unrelated donor were given low-dose anti–T cell globulin. Patients received oral CBD 300 mg/day, starting seven days before alloHCT until 30 days post-alloHCT.

After a median follow-up of 16 months, none of the patients developed acute GVHD while consuming CBD. The cumulative incidence rates of grades 2-4 and grades 3-5 acute GVHD by day 100 were 12.1 percent and 5 percent, respectively, the authors reported. Compared with 101 historical control patients who received standard GVHD prophylaxis alone, the addition of CBD reduced the risk of developing grades 2-4 acute GVHD by 70 percent (p=0.0002).

One year after alloHCT, researchers found that rates of non-relapse mortality at 100 days were 8.6 percent and 13.4 percent, respectively. Among patients who survived longer than 100 days, the cumulative incidences of moderate to severe chronic GVHD at 12 and 18 months were 20 percent and 33 percent, respectively.

The investigators reported that overall compliance was good, with 70 percent of patients taking 100 percent of CBD doses. The main reasons for noncompliance were mucositis and nausea, and no grade 3-4 toxicities were attributed to CBD.

Although the study had some limitations – a single-arm design and retrospective comparison with historical controls – the results highlight “the potential role of CBD in the prevention of GVHD,” according to the investigators. The same investigators are planning another phase II study evaluating the efficacy of oral CBD for the treatment of severe (grades 3/4) acute GVHD. That interventional study will assign patients to one of three arms: oral CBD (150 mg up to 90 days), intravenous methylprednisolone (2 mg/kg/day), and cyclosporine (dose adjusted based on drug trough levels; 200-400 ng/mL) or tacrolimus (dose adjusted on drug trough levels; 5-15 ng/mL).2

The trial’s primary outcome will be the proportion of patients with complete remission of acute GVHD at 90 days. As of November 2017, the study was not yet open for patient recruitment, but the estimated primary completion date is April 2018.


References

  1. Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant. 2015;21:1770-5.
  2.  ClinicalTrials.gov. “Cannabidiol for the treatment of severe (grades III/IV) acute graft-versus-host disease.” Accessed November 2, 2017, from https://clinicaltrials.gov/ct2/show/study/NCT02392780

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