A World of Difference

The slow march to bring high-quality hematology and oncology care to limited-resource areas

The pace of progress in hematology and oncology treatment is dizzying, but advances can only benefit patients who have access to them. While the U.S. and other wealthy countries struggle with costs of treatments, most countries will never see these new therapies, and still work to obtain less revolutionary, cheaper treatments that have been available elsewhere for years.

“Blood cancers and hematologic disorders aren’t considered major public health issues [in limited-resource areas], in part because the surveillance data are not great,” said Satish Gopal, MD, assistant professor of medicine at the University of North Carolina (UNC) School of Medicine in Chapel Hill and cancer program director at UNC Project-Malawi, a collaboration between UNC staff and the Malawi Ministry of Health. “So, unless you’re really looking, these issues are sort of invisible. Even for something as seemingly basic as understanding the burden of sickle cell disease (SCD) in sub-Saharan Africa, the data still largely rely on mathematical modelling.”

In a Blood Advances Talks segment about the delivery of effective care in resource-limited areas, Ami Bhatt, MD, PhD, assistant professor of medicine and genetics at Stanford University, described the issue of global access to cancer treatments succinctly: “For most pediatric patients [with cancer], the most important predictor of 10-year survival is the country in which the child was born.”1

ASH Clinical News spoke with hematologists directly engaged in global health to learn about their work and explore the challenges causing this vast unmet need.

The Global Cancer Burden

“There is a misconception that people in low- and middle-income countries (LMICs), which is approximately 80 percent of the world’s population, mostly die of infection,” Dr. Bhatt told ASH Clinical News.

Yet the data show that as populations age and as communicable diseases become better controlled, the cancer burden in LMICs is growing steadily. Those countries’ health-care needs are shifting accordingly – something that appears to have been overlooked by local governments and international organizations alike.

According to World Health Organization estimates, 70 percent of cancer deaths occur in resource-limited countries and, worldwide, the number of new cancer diagnoses is expected to rise by about 70 percent over the next two decades.2 It is estimated that only 5 percent of global resources for cancer are spent in LMICs.

“If people with cancer, SCD, or other non-communicable diseases are dying and nobody knows about it, and nobody bothers to either measure it or try to do something and then record what happens, then how can it really change?” Dr. Gopal asked. “Patients with cancer in places like Malawi have been invisible to the world until recently, and even now they are barely visible.”

Over the past two decades, UNC Project-Malawi has operated in Malawi’s capital, Lilongwe, to improve the health of Malawian patients through research, education, and efforts to strengthen existing health systems. One of Dr. Gopal’s primary goals in Malawi is to collect better data, with the hope that once staff members measure and establish successful treatment protocols in low-resource areas, local governments and the larger global community will expand access to effective interventions.

“Drugs such as rituximab and growth factors like granulocyte colony-stimulating factor solidly fall into a ‘luxury item’ market.”

—Ami Bhatt, MD, PhD

“Underinsured” Is an Understatement

Many resource-poor areas lack adequate diagnostic and treatment facilities, not to mention trained and specialized staff. According to the African Cancer Registry Network, there are only 102 cancer treatment centers in Africa, 38 of which are located in one country, South Africa.3

“The challenges to providing care range from the lack of trained staff to render a timely diagnosis, administer chemotherapy, and provide supportive treatments such as antibiotics and anti-emetics, to [difficulties] in obtaining a reliable and safe supply of blood products for transfusion, to limited infrastructure within which to provide coordinated care for these complicated patients,” Dr. Bhatt said.

In low-income countries, access to screening and treatment for hematologic disorders and malignancies is often negligible, and only a small minority of these countries have health-care systems capable of delivering the complex care required to manage readily treatable disease – if the necessary drugs are even available.

“Drugs such as rituximab and growth factors like granulocyte colony-stimulating factor solidly fall into a ‘luxury item’ market,” Dr. Bhatt noted.

One example of the incongruity of cancer burden between resource-poor and -rich countries is the prevalence and consequence of Burkitt lymphoma. The malignancy is relatively rare in Western countries but is common in central Africa, where it comes in endemic, sporadic, and immunodeficiency-associated forms. Untreated Burkitt lymphoma is rapidly fatal, but with combination chemotherapy regimens, the response rate can reach 90 percent.

The chemotherapy regimen to treat it includes high doses of cyclophosphamide, doxorubicin, and methotrexate, as well as a high level of supportive care. Because of limited access to those drugs and cultural attitudes, more than half (55%) of parents and guardians of children with Burkitt lymphoma in Cameroon consult traditional healers.4

Other diseases present additional issues: Malnutrition underlies disorders such as iron-deficiency anemia, Dr. Bhatt said, and for malignancies such as diffuse large B-cell lymphomas, access to anti-cancer medications and radiation therapy is often inadequate.

On the Ground in Manila

Although health care is wholly unavailable in many low-income countries, in middle-income countries, physician coverage is often adequate and hospitals are usually well resourced. A lack of widespread insurance coverage means that access to quality care and expensive medications is limited to affluent individuals, though, and the few others who are insured.

Emmanuel Besa, MD, has witnessed firsthand the effects of people being uninsured in the Philippines. Even though there are well-trained physicians and well-equipped hospitals, health-care support from the government is limited, he told ASH Clinical News. Without federal assistance, most of the population is unable to afford the costs of care. The country is just starting to roll out insurance for a wider swath of the population, he said.

Dr. Besa completed his medical training at the University of the Philippines Medical School before doing his post-doctoral studies in hematology/oncology at the University of Pennsylvania and, ultimately, joining the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.

“I think there is a moral issue involved here with how pharmaceutical companies price their drugs in low- and middle-income countries.”

—Emmanuel Besa, MD

On a recent visit to Philippine General Hospital, he met a young woman with relapsed acute myeloid leukemia. She was started on standard 7+3 chemotherapy (cytarabine, daunorubicin), but when the high cost of the medication outpriced her, she had to reduce treatment to an abbreviated five-day schedule.

Another patient referred to Dr. Besa in Manila had to travel to Hong Kong or Singapore to obtain drugs to treat her myelodysplastic syndromes (MDS). “She had the good fortune of being from a wealthy family, but she had to consult a local hematologist to write her prescriptions, which were limited to a month’s supply, and then she had to cover the travel and drug costs,” he recalled.

“I think there is a moral issue involved here with how pharmaceutical companies price their drugs in LMICs,” Dr. Besa said. When he contacted pharmaceutical manufacturers about the pricing of their drugs in the Philippines, he added, “they told me they just don’t offer the option of providing drugs for indigent people like they do in the U.S.”

In some cases, he noted, trials used in the regulatory approval of certain drugs were conducted in lower-income countries like the Philippines, “but once the pharmaceutical companies priced the drugs, nobody could afford them,” he said. “It’s just very unfair.”

Pharma to the Rescue?

The pharmaceutical industry does both more and less than people might think to help patients in resource-poor countries get necessary medications. “Many companies have patient-access programs, but they are clearly too few and too limited to meet the need,” said Dr. Bhatt. “And the access programs are pretty difficult to access, ironically enough.”

From his base in Malawi, Dr. Gopal has had several conversations with pharmaceutical companies about donating medications for his trials, but in the end, the answer has always been no. He has heard similar stories from other global health experts.

“I do think the companies care, but there hasn’t been enough light shone on the problem,” Dr. Gopal said. “I haven’t heard of any attempt to make even drugs that were licensed in the 1990s – like trastuzumab and rituximab – available in low-income countries, even though there are generic biosimilars manufactured in India that have comparable efficacy.”

Drug companies do not market drugs in low-income countries because “it would be pointless for them to do so,” he added. “The Malawi gross domestic product per capita is less than $1 per day, and health expenditure per capita is less than $50 per person per year, compared [with] about $10,000 per person, per year in the U.S.”

Even drug discounting may not be particularly useful. “Rituximab is priced at $35,000, but I am able to buy the Indian biosimilar for my patients for about $3,000 to $4,000,” he explained. “That’s still orders of magnitude different than what is spent on health care in Malawi.”

Dr. Gopal uses grant and philanthropic money to pay for medications for his patients. It is not a sustainable system, but he hopes that his work will show what can be achieved in countries like Malawi. It could lay the groundwork for organizations with deeper pockets, or perhaps a tech billionaire looking for his or her next project, to determine how to fund access to cancer medicines.

The situation seems dire, he said, but there is reason to hope that the situation will improve. The HPV vaccine, for example, is now available in sub-Saharan Africa at substantially lower costs than in the U.S. because of multilateral negotiated agreements.5

Even more encouraging is the example set by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), which has provided HIV testing and counseling to 56.7 million people and is supporting life-saving treatment for 7.7 million people since its inception in 2003.6

“Nothing like PEPFAR exists for blood diseases, either malignant or non-malignant,” Dr. Gopal said. “Even hydroxyurea is often unavailable for patients with SCD in many parts of sub-Saharan Africa.”

Both Drs. Gopal and Bhatt believe that new patient-access programs sponsored by pharmaceutical companies, such as the Pfizer-Cipla program and the Glivec International Patient Assistance Program, are steps in the right direction. (See SIDEBAR for more information about the programs.)

“I would say [the Pfizer-Cipla program] is a first break in the clouds,” Dr. Gopal said. “We need to celebrate these early successes, but we have to recognize that this program alone isn’t yet adequate to bring high-quality care to these patients.”

According to Dr. Besa’s hematology colleagues in Manila, even though patient-access and discounted drug programs are available in the Philippines, about 20 percent of CML patients are given hydroxyurea instead of imatinib because of cost concerns. In some cases, the patients might be connected to “grey-market” sources who can access generic medicines from India. “When I was asked recently to give a talk in Manila, I realized that all the drugs I was going to talk about are not affordable there,” he said. “I felt very frustrated.”

Low-Hanging Fruit

It’s not often that a simple-to-implement and inexpensive new treatment protocol is associated with a 90 percent reduction in death. The hematology world glimpsed the outsized benefits of “simple solutions” at the 2016 ASH Annual Meeting, when Eugenia Vicky Asare, MBChB, a hematologist at the Korle Bu Teaching Hospital in Accra, Ghana, presented a study conducted in pregnant women with SCD in Ghana.7

For Ghanaian women with SCD, morbidity and mortality associated with pregnancy are about 11-fold higher than that of Ghanaian women without SCD. To reduce the burden, Dr. Asare and researchers developed a multidisciplinary team approach that included admitting patients only to select wards in the hospital and facilitating timely transfer to the intensive care unit, when needed. The team included obstetricians, hematologists, pulmonologists, nurses, and midwives.

The results speak for themselves: With their relatively low-tech, multidisciplinary approach to improve care for pregnant women with SCD, mortality fell by 89.1 percent (p=0.007). Perinatal mortality decreased from 60.8 per 1,000 total births at pre-intervention to 23.0 per 1,000 total births at post-intervention, representing a 62.2 percent risk reduction (p=0.2).

Some of their fixes were incredibly simple: “We realized that about 60 percent of these patients died from cardiopulmonary complications, and acute chest syndrome was the major event,” Dr. Asare said in an interview with ASH Clinical News at the 2016 annual meeting. “Recognizing this, we [instituted a policy of] using latex balloons as incentive spirometry, because incentive spirometry in itself is expensive.”

The new protocols involved “no added costs and no expensive technologies,” she added, “so I think it will be easy to replicate [as long as] you really have it in mind to help these patients.”

In an update to be presented at this year’s annual meeting, Dr. Asare and colleagues will share new data demonstrating that the multidisciplinary approach has allowed clinicians to reduce maternal and perinatal mortality rates in Ghanaian women with SCD to levels similar to women without SCD.8

A Multifaceted Approach

Dr. Bhatt feels strongly that, although the world needs expanded access to medications, drugs are far from the only issue needing attention in LMICs.

In addition to her work at Stanford, Dr. Bhatt is the co-founder and co-president of Global Oncology (GO), a non-profit that addresses the disproportionate share of the global cancer burden shouldered by LMICs. She co-founded GO with Franklin Huang, MD, PhD, during her hematology and oncology fellowship at the Dana-Farber Cancer Institute in Boston.

Diagnostics are lagging far behind in many countries, she noted. Immunohistochemistry and flow cytometry, which are particularly important for hematology care, can be difficult to access and costly, and few lower-resource countries have working radiation-therapy systems.

“While drug access is a major issue, it is by no means the only issue,” Dr. Bhatt said. “Once drug access is solved, we will quickly realize that we still can’t deliver high-quality care because we are missing a lot of other pieces.”

It is also unrealistic to think that cancer care has to fall by the wayside in limited-resource countries just because so much is needed just to raise the level of basic care. It’s not “one or the other,” she said. “Of course, I think it’s critically important to address malnutrition, infant mortality, and other such issues, but I think we should be careful not to create a false dichotomy.”

GO aims to facilitate a collaborative environment and break down silos so that people with the will to get involved can work together to find solutions.

“Addressing cancer and hematology care properly should be a priority, in part because of the economic burden these diseases place on patients and their families,” Dr. Bhatt said. “Sick patients do not say, ‘I have cancer, but I’m not going to seek care.’ What they do is bankrupt themselves, their extended families, and their supportive communities to pay for care, and it is often too little and too late.”

One of GO’s flagship projects is the GO Map, a web-based platform that catalogs international cancer research, care, and outreach programs (FIGURE).9 At the time of publication, it listed and described 3,981 projects worldwide. “My heart breaks for [patients with] CML who have to be switched from imatinib to hydroxyurea. With the stroke of a pen on a prescription pad, we shorten their lifespan by 25 years,” she said. “We are lucky – we have an opportunity to collaboratively do something to change this.”—By Debra L. Beck


References

  1. Bhatt AS. Technological solutions for global hematology and oncology. Blood Advances. 2017;1:396.
  2. World Health Organization. Cancer fact sheet, February 2017. Accessed November 5, 2017, from http://www.who.int/mediacentre/factsheets/fs297/en/.
  3. Stefan DC. Cancer care in Africa: an overview of resources. J Glob Oncol. 2015;1:30-6.
  4. Afungchwi GM, Hesseling PB, Ladas EJ. The role of traditional healers in the diagnosis and management of Burkitt lymphoma in Cameroon: understanding the challenges and moving forward. BMC Complement Altern Med. 2017;17:209.
  5. Jim JJ, Campos NG, O’Shea M, et al. Model-based impact and cost-effectiveness of cervical cancer prevention in sub-Saharan Africa. Vaccine. 2013;31:F60-72.
  6. Using data to deliver on an AIDS-free generation. Accessed November 5, 2017, from https://www.pepfar.gov/documents/organization/266089.pdf.
  7. Asare EVNK, Adomakoh Y, Olayemi E, et al. Prospective implementation of multi-disciplinary obstetric team decreases the mortality rate of pregnant women with sickle cell disease in Ghana. Abstract #1017. Presented at the ASH Annual Meeting and Exhibition, December 5, 2016; San Diego, CA.
  8. Oppong SA, Olayemi E, Adomakoh Y, et al. Multi-disciplinary obstetrics and sickle cell disease clinic in low resource setting lowers maternal and perinatal death rates to the same levels as those without sickle cell disease. Abstract #616. Presented at the ASH Annual Meeting and Exhibition, December 11, 2017; Atlanta, GA.
  9. Global Oncology. The GO Map. Accessed November 5, 2017, from http://globalonc.org/Projects/global-cancer-project-map/.

 

Pharmaceutical companies engage in patient-assistance programs to bring life-saving medications to patients in limited-resource countries. Two initiatives are taking innovative steps to improve patient access.

The Glivec International Patient Assistance Program

The Glivec International Patient Assistance Program (GIPAP) was established in 2002 by Novartis and the Max Foundation, a non-profit, non-governmental organization, to make imatinib accessible to all medically and financially eligible patients in more than 75 countries. To date, more than 78,000 patients with chronic myeloid leukemia (CML) have benefited from GIPAP.1

In late September 2017, Novartis and the Max Foundation announced their intention to replace GIPAP with a new collaboration, called CMLPath to Care, which will continue to provide access to imatinib in the developing world, along with secondline nilotinib for approved indications.2

The Pfizer-Cipla Program

In June 2017, the American Cancer Society and the Clinton Health Access Initiative (CHAI) announced two separate groundbreaking market-access agreements with pharma giant Pfizer and Mumbai-based Cipla Inc.3 The agreements steeply discount the prices of 19 cancer medicines in Ethiopia, Nigeria, Kenya, Uganda, Rwanda, and Tanzania.

Negotiated by CHAI, the agreements are part of a broad effort to improve access to cancer care throughout Africa. “While cancer treatments and the tools for early diagnosis are readily available in developed countries, market forces and other barriers [lead to] limited access in Africa,” CHAI Chief Executive Officer Ira Magaziner said in a statement. “As was done for the HIV/AIDS crisis before it, this public-private collaboration will help revolutionize cancer treatment in sub-Saharan Africa and has the potential to save thousands of lives each year.”4

As an added benefit, a group of top U.S. oncologists are set to simplify cancer-treatment guidelines for underequipped African hospitals. Their protocols will then be built into an online tool available to any oncologist with internet access.

The agreement with Pfizer will give discounted access to the following medicines: carboplatin, cisplatin, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, leucovorin, methotrexate, oxaliplatin, and paclitaxel.

The Cipla agreement covers anastrazole, bleomycin, capecitabine, carboplatin, cisplatin, cytarabine, oxaliplatin, and vinblastine.

Pfizer has agreed to charge prices that are just above its manufacturing costs, and Cipla has said it will provide some oral medications for just 50 cents per pill and some infusions for $10 per dose. Cipla hopes to start manufacturing the drugs at its factories in Uganda and South Africa.


References

  1. The Max Foundation. Glivec® International Patient Assistance Program (GIPAP). Accessed November 4, 2017, from https://www.themaxfoundation.org/what/treatment/glivec-international-patient-assistance-program-gipap/.
  2. Novartis and the Max Foundation transform pioneering cancer access program for people in lower-income countries. Accessed November 4, 2017, from https://www.novartis.com/news/media-releases/novartis-and-max-foundation-transform-pioneering-cancer-access-program-people.
  3. American Cancer Society. American Cancer Society and Clinton Health Access Initiative announce collaborations with Pfizer and Cipla to increase access to lifesaving cancer treatment in Africa. Accessed November 4, 2017, from http://pressroom.cancer.org/2017-06-20-American-Cancer-Society-and-Clinton-Health-Access-Initiative-Announce-Collaborations-with-Pfizer-and-Cipla-to-Increase-Access-to-Lifesaving-Cancer-Treatment-in-Africa.
  4. McNeil DG Jr. As cancer tears through Africa, drug makers draw up a battle plan. New York Times. Accessed November 4, 2017, from https://www.nytimes.com/2017/10/07/health/africa-cancer-drugs.html.

ASH offers a wide array of programs and services to help hematologists conquer blood diseases worldwide. These include programs that place ASH members in volunteer positions educating and training hematology personnel in the developing world, as well as programs that open U.S.-based hematology training to foreign-trained physicians. For full details about these initiatives, visit hematology.org/Global.

The ASH Global Research Award

The ASH Global Research Award is designed to support future international scientific leaders, increase hematology capacity, and nurture global collaboration. The award is intended to support hematologists between completion of training and the establishment of their independent careers. It is accessible to individuals across geographical regions.

Visitor Training Program

The Visitor Training Program helps build hematology capacity in developing countries with the goal of improving patient care. The program provides funding for hematologists or hematology-related health-care professionals in the developing world to receive training on a specific topic or technique for up to 12 weeks. Training is carried out in the clinic or laboratory of an ASH member under the ASH member’s supervision and mentorship. Upon completion of training, participants return to their home institutions to implement the skills and knowledge they acquired to address the specific hematology need.

Latin American Training Program

The Latin American Training Program is intended to build hematology capacity in Latin America around specific priority areas for the region. The program provides funding for hematologists or hematology-related health-care professionals in Latin America to receive training in one of the following areas: Flow Cytometry and Molecular Biology, Adult Stem Cell Transplantation, Diagnosis and Treatment of Coagulopathies, Thrombosis and Hemostasis, or Pediatric Stem Cell Transplantation.

Health Volunteers Overseas

ASH partners with Health Volunteers Overseas, a non-profit organization dedicated to improving global health through education, to bring consultation and training to hospitals in the developing world. Training provided by ASH members takes the form of rounds in clinics, bedside consultations, classroom lectures, laboratory visits, and more. The objective is to develop sustainable improvement in the management of hematology patients at institutions in developing nations.

ASH Global Capacity-Building Showcase

The Global Capacity-Building Showcase is a new poster category at the ASH annual meeting designed to showcase research and capacity-building initiatives in low- and middle-income countries. Posters will be presented in an electronic format and will highlight existing partnerships with measurable outcomes. Posters will be available for viewing at the following times during the 2017 ASH Annual Meeting:

  • Saturday, December 9: 9:00 a.m. – 7:30 p.m.
  • Sunday, December 10: 9:00 a.m. – 8:00 p.m.
  • Monday, December 11: 10:00 a.m. – 8:00 p.m.

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