ASH in Cuba: Unmasking Challenges and Opportunities in Hematology

On December 17, 2014, President Barack Obama and President Raúl Castro announced a diplomatic reboot between the United States and Cuba. This warming of relations led to the re-opening of each countries’ embassies in the summer of 2015, and a series of intergovernmental dialogues aimed at addressing broad matters of concern such as cooperation in law enforcement and counterterrorism, human and civil rights, legal and safe transnational migration, environmental protection, economic development (including accelerated telecommunications/internet penetration), and expansion of travel and mail service between the two countries. Recently, the first cruise ship in 50 years sailed to Cuba from an American port, and plans have been set for 110 direct round-trip commercial flights a day.

Renewed hope exists that this more free exchange of human and economic capital will catalyze democratic-style reforms across sectors of Cuban society. However, it remains unclear what the pace and degree of such change will be. Failure of the Cuban economy is multifaceted, including decades of isolation and sanctions by the U.S. (although relationships with many Latin American countries and some European nations have persisted), loss of subsidized trade and aid from the Soviet Union and former East bloc, and burdens imposed by the authoritarian regime. These factors have contributed to Cuba’s 11 million citizens living in cramped and crumbling dwellings with a resource-poor existence based on rationing of food, medical supplies, and other basic necessities.¹  Although the colorful sea of 1950s Fords, Cadillacs, and Oldsmobiles that blanket Cuba’s streets may tug at one’s nostalgic heartstrings, these temperamental cars, resuscitated by makeshift parts, affirm that the country is largely stuck in the past. Nonetheless, there is a sense of palpable excitement regarding Cuba’s future prospects. As ASH President Dr. Charles Abrams notes in his column (see page 2) it is during this dynamic period of rapprochement with the U.S. that ASH felt a unique opportunity existed to visit Cuba to advance its global mission of hematology education, patient care, and research. I accompanied ASH’s executive committee and senior staff to the annual Executive Committee Spring Retreat, held this year in Havana.

One of the highlights of the retreat was an educational exchange with some 40 members of the Cuban Society of Hematology (CSH). The CSH consists of 294 members, including 154 hematologists who serve at 39 clinical facilities (25 adult and 14 pediatric hospitals) in all provinces of the island nation. The agenda was comprised of a translator-facilitated discussion of the American and Cuban approaches to the management of three hematologic diseases. Drs. Alexis Thompson and Sergio Machín García discussed sickle cell disease; lectures on acute myeloid leukemia and acute promyelocytic leukemia were delivered by Drs. Marty Tallman and Carlos Hernández-Padrón; and Drs. Alison Loren and Alejandro González Otero gave updates on acute lymphoblastic leukemia. I had the opportunity to learn more about the practice of hematology in Cuba from the President of the CSH, Dr. Antonio Bencomo. I was particularly interested in having him paint a picture of how the decades-long economic squeeze of the Cuban economy has impacted the availability of medicines commonly used in the U.S. as part of standard care approaches to malignant and nonmalignant hematologic disorders.

Dr. Bencomo reiterated that the Cuban health-care system guarantees all of its patients “necessary” medicines according to the precept of universal and free care. Expensive medications that constitute a second- or third-line therapy may be available through treatment protocols established through Cuba’s national system of health and medical specialties. In many cases, access to new drugs is difficult because of the limitations placed upon companies to restrict their sale to Cuba. The 1992 Cuban Democracy Act made it more difficult to purchase medications from U.S. companies or their foreign subsidaries.¹  The 1996 Congressional Helms-Burton Act stipulated that any non-U.S. companies (including pharmaceutical and biotechnology firms) were subject to lawsuits in U.S. courts if they engaged in trade with Cuba.^1,2  Because the overwhelming majority of drugs are either produced in the U.S. or by European companies that have merged with U.S. firms, this decimated Cuba’s access to medicines, vaccines, medical devices, and diagnostic equipment. Although the U.S. has provided humanitarian donation of medicines and medical supplies, and authorizations for some medicines have been granted, complicated banking, licensing, and shipping policies frustrate the import of such lifesaving materials.

Cuban resourcefulness and self-reliance have overcome some of the external limitations imposed on access to drugs. The Centro de Immunologia Molecular (CIM), which opened in 1994, is Cuba’s premiere research, production, and biotech campus. CIM’s biotechnology focus is on mammalian cells, as well as the production of monoclonal antibodies and cancer vaccines. Their paradigm is to use treatments such as immunotherapy as a means of making cancer a chronic disease, with less of a focus on cure. It has 1,136 employees and houses laboratories and animal facilities. CIM is part of the CUBABIOPHARMA holding group that has 21 products in the pipeline (six registered) and 48 patents, and exports products to 31 countries. There are 78 manufacturing facilities, including several in other countries (such as Japan and Brazil). In all, it has 21,785 workers, of whom 262 have PhDs. The Roswell Park Cancer Institute and Moffitt Cancer Center have existing drug development partnerships with CIM.

Dr. Bencomo pointed out that Cuban biotechnology also produces and commercializes erythropoietin (ior-EPOCIM^®) by CIMAB SA, and filgrastim (Hebervital^®) by Heber Biotec SA. Arsenic (Arsenin^®) is also produced domestically; it has been added to ATRA, which was incorporated by Cuba into APL therapy in 1991 (one of the first countries to do so). For patients with venous thromboembolism, low-molecular weight heparin and coumadin are available, with the latter also being produced by the Cuban pharmaceutical industry. The new oral anticoagulants are not widely available, but may be given to patients after failure of initial treatment. Dr. Bencomo provided some additional disease-specific examples of available therapies in Cuba:

• Chronic myeloid leukemia. All patients are treated with imatinib (Gleevec^® or generic). Resistant patients are given nilotinib; standard or pegylated forms of interferon-α are available (Heberon Alfa R^® ; PEG-Heberon) and produced by Cuban biotechnology (Heberbiotec SA).

• Chronic lymphocytic leukemia. Patients younger than 60 years receive fludarabine, cyclophosphamide, and rituximab; cyclophosphamide, vincristine, and prednisone is administered to patients older than 60 years. Ibrutinib and idelalisib are still not considered front-line therapy and could be made available after an unfavorable response to conventional therapy.

• Myelodysplastic syndromes. In addition to the aforementioned use of Cuban-manufactured erythropoietin and filgrastim, thalidomide is often the first choice for lower-risk MDS, including del(5q) MDS. Azacitidine is the first-line therapy for higher-risk MDS and a second-line option for subjects with lack of response or intolerance to thalidomide. After failure of these “conventional” agents, access to lenalidomide or decitabine is possible. For MDS and other diseases, there are 46 blood banks in the country that provide blood components from voluntary donors.

Flow cytometry, standard karyotyping, fluorescence in situ hybridization, and molecular analyses are all available for the diagnosis of hematologic malignancies. Patient samples are sent for central analysis at the Institute of Hematology and Immunology (IHI) in Havana. The IHI, a research institute created in the 1960s by the Ministry of Public Health, leads the national effort in scientific investigations of hematologic diseases (e.g., sickle cell anemia, hemophilia, leukemias) and immunologic disorders. In addition to establishing quality assurance standards for transfusion medicine, histocompatibility testing, and related fields of immunohematology, IHI's mission is to provide postgraduate training of physician in hematology and training of health technologists to cover the nation’s needs in these subspecialty areas. The IHI interdigitates well with Dr. Bencomo’s stated mission of the CSH—to ensure the scientific development of its members so that they can satisfy the needs of their patients. CSH, in conjunction with the IHI and their National Hematology Group (Grupo Nacional de Hematologia), project labor needs in the areas of hematology, immunology, transfusion medicine, and regenerative medicine. He cited that CSH’s area of greatest interest is the use of advanced technology to improve diagnosis and to achieve a greater percentage of cures for patients with hematologic malignancies, including the use of unrelated donor and haploidentical hematopoietic cell transplantation.

Dr. Bencomo touched on the feasibility of conducting clinical trials in Cuba. He indicated that the country has a guiding Center of Clinical Trials (CENCEC) which belongs to the Ministry of Public Health (MINSAP). It is responsible for the coordination and implementation of clinical trials for all medical specialties, including hematology, and ensuring compliance with international clinical trial standards. There is also a public registry of clinical trials that is accessed through the portal of Infomed (http://registroclinico.sld.cu/). Dr. Porfirio Hernández and colleagues from the IHI have led Cuba’s clinical trial efforts in regenerative medicine. Since 2004, they have studied the effects of intramuscular or intra-arterial administration of autologous bone marrow mononuclear cells (BM-MNC) or peripheral blood MNC mobilized from the BM with filgrastim.³  The indications for treatment have included critical lower limb ischemia due to arterial insufficiency with criteria for amputation; lymphedema; orthopedics and trauma (bone cysts, complex bone fractures, aseptic necrosis of the hip and degenerative joint injuries); periodontitis; and paraplegia due to spinal cord injury. Dr. Hernández cited that in 73 percent of patients with critical lower limb ischemia and criteria of major amputation, this intervention was avoided; in patients with intermittent claudication, improvement was obtained in 85 percent of cases.⁴  Their group has also evaluated the role of platelets in regenerative medicine. By the end of 2014, 5,533 units of platelet components, primarily for orthopedic and “angiology” indications had been used for such trials.⁴  Other regenerative uses of platelets have included burns; skin ulcers; and in the form of eye drops for treatment of injuries of the cornea and dry eye due to low production of tears. In the decade following treatment of the first patient in 2004, the number of units supplied either with stem cells, platelets, or both combined, reached 13,045, making Cuba among one of the nations with the most widespread application of regenerative medicine.⁴  Randomized, controlled trials are needed to definitively establish the efficacy and safety of these regenerative medicine efforts.

The highly advanced training of Cuban doctors is widely acknowledged. Cuba has one of the highest ratios of doctors to residents in the world, and the country places a high priority on medical care, like it does for education. However, it is also well known that doctors’ pay, like that of everyone else in society, is exceedingly low and is a major impetus for the exodus of medical trainees to the U.S. and other countries. In 2014, after cutting 100,000 redundant jobs, the Cuban government hiked the monthly salaries of nurses and doctors by 150 percent: from $13 to $25 for entry-level nurses and up to $60 for nurses with the most experience; and from $20 to $30, up to $60 to $70 for the most highly trained specialty doctors.^5,6  Cuba uses its quality doctors, nurses, and ancillary health specialists to feed its biggest generator of foreign revenue (roughly $8 billion), the export of some 50,000 medical workers to 66 countries around the world. These overseas postings provide an opportunity for medical professionals to develop increasing expertise in global health, and to earn more income; however, their salaries are often less than what nationals from other countries receive for similar work. In line with Cuba’s strong global footprint, CSH has made a strong effort to foster partnerships with international medical societies such as the Inter-American Division of the International Society of Hematology; the World Federation of Hemophilia; the Latin American Cooperative Group of Haemostasis and Thrombosis; and the Caribbean Researchers Network on Sickle Cell Disease and Thalassemia.

ASH’s international exchange with CSH was a successful stepping stone for future joint scientific meetings and research projects. However, in order to obtain a more in-depth appreciation of Cuba’s practice of hematology, “in-country” immersion with Cuba’s health-care officials in their practice settings will be critical. To this point, ASH Treasurer Dr. Susan Shurin, who is also senior advisor in the Center for Global Health at the National Cancer Institute, returned to Cuba shortly after the retreat as part of a separate, non-ASH U.S.-Cuba dialogue on health and cancer, sponsored by the American Association for the Advancement of Science (AAAS) and CIM. She had an opportunity to meet with officials from MINSAP, the Dean and faculty of the National School of Public Health, and she toured the National Institute of Oncology of Radiobiology (INOR) with their leadership. INOR is one of the two major tertiary care centers in Havana and specializes in treatment of pediatric and gynecologic cancers. They have radiotherapy facilities including several linear accelerators, and a new PET-CT scanner. Most of the machinery originates from Europe, as do the PhDs earned by their highly educated staff. The Hermanos Ameijeiras Hospital is Cuba’s major referral center for solid tumor and bone marrow transplantation, with almost 300 transplants performed to date primarily for leukemias, myeloma, and lymphomas. Referrals to such secondary or tertiary care centers originate from so-called local “polyclinics,” which are basic, but well-staffed primary care doctors’ offices that dot Cuba’s provinces.

Dr. Shurin came away very impressed with the Cuban infrastructure and personnel. Although the sojourn in Cuba was brief, ASH senior staff and the Executive Committee developed similar impressions, and developed a warm affinity for our brethren Cuban hematologists and the people at large. ASH is energized by the opportunities for clinical and scientific collaboration that lie ahead, especially for trainees, who need only travel 90 miles over the Straits of Florida.