A.
Research Plan
1.
Significance and Innovation
What is the research question to be addressed?
The question: Can advanced treatment such as stem cell transplantation for sickle cell disease be exported to/implemented in developing countries?
We are proposing to improve the care of sickle cell patients in low- and middle-income countries
(LMIC) by creating a transferrable model of a stem cell transplantation center for this population. The pilot center will be developed in Nepal, in collaboration with the Binaytara Foundation and Civil
Hospital, Kathmandu, Nepal.
The goal of this research is to determine a capacity building model, strategy and implementation plan that can be utilized to improve care and treatment for sickle cell patients globally.
How will the proposal further the understanding of the mechanism of disease in sickle cell, contribute to the development of new therapies, or improve patient care?
Severe congenital hematologic diseases such as sickle cell anemia or thalassemia cause severe organ damage and ultimately the death of young adults with these diseases. In addition, quality of life is severely affected by frequent hospital admissions, acute pain, difficulties in achieving education and life goals, and significant costs for families and the society providing for these patients.
Transplantation of hematopoietic stem cells from compatible donors is the only cure for sickle cell disease or thalassemia. This procedure was limited in the past by toxicity associated with chemotherapy included in any standard transplant preparative therapy. Following an NIH study, we have successfully adopted a strategy that allows us to transplant sickle cell patients without chemotherapy and achieve a cure rate greater than 90 percent.
Why is your proposal innovative? How does your proposed research differ from the dominant concepts prevalent in the field or build upon them?
Lack of infrastructures and poor social and economic conditions determine limited access to care and short survival of patients affected by congenital severe diseases in India or Nepal. Through the efforts of an international network our institution is now connected to a hematologic center in Kathmandu
(Nepal). A multi-step plan was designed with the aim of creating in 2 years the first center in the
India/Nepal area to offer a chemotherapy-free stem cell transplant for patients with sickle cell or thalassemia: continuous education process through telemedicine, 6-12 months rotations of personnel in our sickle cell and transplant centers, and multiple site visits in Nepal to assist the initial transplants in the third year. We anticipate that this project will allow India and Nepal to significantly improve the outcome of patients with blood disorders.

2.
Hypotheses and Specific Aims:
State the hypotheses that form the basis for the research and the specific aims that you intend to accomplish with the award
Hypothesis:
Chemotherapy-free stem cell transplantation can be applied in sickle cell patients without severe complications in an LMIC setting when an appropriate treatment center is established.
Specific Aims: a. To transfer the knowledge of diagnostic and therapeutic methodologies to address sickle cell in Nepal b. To train clinical and professional staff using in-person instruction, web-based resources, and a trainthe-trainer model both on-site in the US and in Nepal, and to create tools for assessment, quality indicators and for Institutional Board Review (IRB)/ Hospital Ethical Committee applications c. To develop the capacity to establish a bone marrow transplantation Center in Nepal, with a particular focus on using stem cell transplantation to address treatme n t of sickle cell disease, and to open that
Center in year 3 of the project.
3.
Background:
Discuss the scientific knowledge that led to the stated hypotheses and specific aims and cite critical references.
The results of standard (chemotherapy-based) transplants in Sickle Cell Disease have been limited in the past by the morbidity/mortality, especially in adult patients, due to organ toxicity post chemotherapy and infection. However, recent studies (Freed et al 2012) suggest that allo-SCT from
HLA-matched sibling donors may provide a solution.
Nepal is located in South Asia between India and China. According to 2011 census, Nepal’s population is 26.5 million. Numerically, Indo-Nepalese (Migrants from India) are the dominant group with more than 50% of total population (http://lcweb2.loc.gov/cgi-bin/query/r?frd/cstdy:@field(DOCID+np0048). India has one of the largest sickle cell anemia patient populations. There is no official data on prevalence of sickle cell disease in
Nepal. Dr. Bishesh Poudel, one of the two hematologists in the country states that he sees two to three sickle cell patients every week. Since the majority of people in the country are migrants from India, sickle cell population in Nepal is likely to be large. Besides this, Indians have easy and visa free access to Nepal. A Stem cell transplant center in Nepal will be provide care to patients from Nepal and India both.
4.
Preliminary Data (not required)
Following the initial report in the New England Journal of Medicine at the end of 2009, showing the results of 10 sickle cell adult patients transplanted at the National Institute of Health (NIH), in
November 2011, the University of Illinois Hospital BMT program enrolled its first subject into a phase
I/II study of non-myeloablative allogeneic stem cell transplantation for aggressive sickle cell disease.
The study involves a chemotherapy-free stem cell transplant from a matched related donor. In this procedure, hematopoietic stem cells obtained from the peipheral blood of the donor cells are transplanted into the patient after an immunosuppressive therapy with a monoclonal antibody (anti-
CD52, alemtuzumab) and a low dose of total body irradiation (3 Gy total). Possible donors must be

full siblings and completely HLA compatible and with either no sickle cell or with heterozygous disease (sickle cell trait).
As of this writing, approximately 35 patients at the NIH and 5 patients at UIH have undergone this innovative type of transplant. In the NIH expanded experience communicated at meetings, there is a
10% rejection, in our experience on 4 transplants (the 5th still too early to assess clinical outcome), all the patients engrafted donor cells. With a follow-up of 9 to 18 months, all have normal levels of hemoglobin, In 3 patients where the donor had a normal Hgb, sickle cell (HgbS) has disappeared since approximately 90 days following the transplant. In the patient whose donor is a sickle cell trait, current level of Hgb (9 months after transplant) is within normal range and he has become a sickle cell trait.
Importantly, because of the absence of chemotherapy in the pareparative regimen, these patients do not experience significant changes in the white cell count, or anemia or thrombocytopenia, and the post transplant course has been mostly uneventful. Particularly, not having profound neutropenia
(ANC <0.5 x 10^9/L), the risk of infection is minimal and patients can be discharged home very soon.
In 2 patients we observed a delayed neutropenia for 2 days which resolved very quickly. These patients need to be observed initially to monitor pain crises or infections, but their management is without major complications and they experience a rapid improvement in their quality of life.
Our experience is consistent with achievement of a full donor engraftment of donor myeloid cells
(including erythroid cells) and a mixed stable engraftement of donor and host lymphoid cells. This is also the reason for not observing any graft-versus-host disease.
We feel that our results, and results of other studies mentioned in the application, provide sufficient justification for the dissemination of this procedure to other parts of the world where sickle cell patients can benefit from our experience.
5.
Research Design and Methods:
Describe the procedures and methodology that will be used to accomplish the specific aims of the project.
During each of the first two years 1 and 2 of the project, two teams of trainees will come to Chicago to participate in the project. During this time, they will become familiar with the state of the research, and to develop the skills associated with stem cell transplantation in sickle cell patients. These trainees will work in the UIH Blood Bank and bone marrow stem cell Transplantation Center, will become familiar with the comorbidities and epidemiology of sickle cell
—especially as it applies in
India and Nepal —and will establish methodologies for ongoing communication and training once they return to their home country. Each group of Nepalese trainees that comes to UIH for training will include two nurses and two physicians; also, a data manager/patient coordinator will join one of the groups in year 1.
The training period will last approximately 8 weeks. During that time, the clinicians will not only be participating in educational programs to advance their skills and knowledge, but also will be taking part in an intensive train-the-trainer program; this will enable them to enroll and educate additional physicians and nurses at the Center in Nepal.
The Binaytara Foundation (BTF) and Civil Service Hospital, Nepal have partnered in a project to develop the country’s first Blood and Marrow Stem Cell Transplant (BMT) Center.
Stem cell transplant is a standard procedure for the treatment of many blood cancers. The planned BMT center in Kathmandu will aim to serve not only the 30 million people of Nepal but also millions of people from

neighboring India. A block of 5 patient rooms at Civil Hospital has been allocated for the care of patients who will receive BMT. Through this project, we will provide the capacity to staff the Center and offer continuing education to clinicians.
Follow-up with the trainees once they return to Nepal will be conducted via teleconference, Skype, and web-based initiatives. Currently, a collaboration between UIC and BTF has resulted in a series of continuing medical education webinars related to hematological topics; additional sessions focused on sickle cell disease will be developed during the project and offered regularly to staff
Each year, UIH physicians will travel to Nepal to continue the training and assist in the establishment of the clinic and the staffing development. A needs assessment will be conducted to foster the creation of a patient education program. Technical support will also be provided to the data manager/transplant coordinator during these visits.
Discuss any potential difficulties and alternate approaches that might be taken to accomplish the goals.
The success of UIC’s Hematology/Oncology Fellowship Program in attracting and training top researchers and clinicians demonstrates the capabilities within UIC to conduct the proposed program.
Our faculty and staff have extensive experience in international work, and the collaboration with the
Binaytara Foundation will facilitate the exchange process with Nepal.
If you are proposing a clinical study, details on the study design, sample size, subject inclusion and exclusion criteria, and plans for patient recruitment must be included.
In this application, we are not proposing a specific clinical study. Rather, we will utilize the ongoing work of the PI and the UIC Stem Cell Transplant team as a model for the Center we plan to establish in Nepal.
6. Timeline:
1.
Cited Literature (does not count toward the page limit)
Freed J, Talano J, Small T, Ricci A, Cairo MS. Allogeneic cellular and autologous stem cell therapy for sickle ce ll disease: ‘whom, when and how.’
Bone Marrow Transplantation (2012) 47, 1489
– 1498
B.
Resources (maximum 1 page)

The University of Illinois Hospital and Health Sciences System Blood & Marrow Transplant Program is accredited by the Foundation for the Accreditation of Cellular Therapy. Founded in 1996, FACT establishes standards for high quality medical and laboratory practice in cellular therapies. FACT is a non-profit corporation co-founded by the International Society for Cellular Therapy (ISCT) and the American Society of Blood and
Marrow Transplantation (ASBMT) for the purposes of voluntary inspection and accreditation in the field of cellular therapy.
From its founding in 1997, the UIC Peripheral Blood and Bone Marrow Stem Cell Transplant Program has treated more than 550 patients with different types of cancer of the bone marrow, specific solid tumors (e.g. testicular cancer) or non-neoplastic blood disorders, such as aplastic anemia or sickle cell anemia. The
Progam hosts a 3-year ACGME accredited Hematology-Oncology Fellowship.
A remodeled 10-bed Bone Marrow Transplant Unit opened at UIC in 2012; this facility for patient care is supplemented by a state-of-the-art Stem Cell Processing/Bone Marrow Collection Laboratory, Blood Bank, and Clinical Transplant Services Center. Specialized equipment includes [more]
C.
1.
·
Budget Justification and Key Personnel (maximum 1 page)
Budget justification
Include a short explanation of the principal investigator and co-principal investigator (if applicable) time spent on the grant.
·
·
If there are co-principal investigators on the grant, please indicate their role.
Explain large or unusual budget allocations and other expenses that may not be self-evident. You do not need to provide a detailed justification of the entire budget.
2.
·
Key Personnel
Indicate the role and institution of co-investigators, consultants, and collaborators under key personnel, if applicable
Budget Justification
The PI and Co-PI will be dedicating 10-15% of their time to this project over the course of the three years. Dr. Rondelli, the PI, will direct the project, and supervise the training of the Nepalese clinicians and the data manager/transplant coordinator. Dr. Erickson, the Co-PI, will be responsible for the online training program, and will act as liaison with Dr. Shah [consultant, see below] and the hospital in
Nepal. He will also supervise the activities of the project administrator, who will be monitoring budgets and processing financial transactions related to the project.
The most significant expenditures on the project are related to the travel and training of the Nepalese clinicians. In each of the first two years of the project, 9 participants will come to the US for intensive training over a period of 2 months. In addition to the cost of airfare [approximately $2,000 per person round trip], we estimate an additional $150 per day for lodging, meals, and incidentals while in
Chicago. When UIC faculty and project consultants travel to Nepal [3 visits per year], we anticipate similar costs.
Educational materials will be developed and provided to all participants, and ongoing web-based
Continuing Medical Education courses will also be created and implemented.
It is important to note that most of the funds are being spent on trainee travel and educational materials. We are requesting a small amount of salary funding for the PI, Co-PI, a Heme/Onc Fellow

to assist in the training, and for an administrator. The consultant, Dr. Binay Shah, will receive no salary, but will be funded to travel to Nepal during each year of the project.
D.
NIH format biographical sketch
A biographical sketch must be submitted only for the principal investigator and for the co- principal investigator if applicable.
· 10-point size font may be used to complete this section
· Each biographical sketch may not be longer than four pages.
· Each biographical sketch must include: o The investigator’s name and position title, education and training information (earliest
· training and degree), research and professional experience (concluding with the current position)
A personal statement that describes the investigator’s most innovative and/or significant research/experience
.
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·
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Complete references to original peer -reviewed scientific reports only; highlight first author
(or equivalent) publications. No reviews, chapters, books or abstracts should be listed.
If you have more peer -reviewed original publications than can be listed, list those most directly related to the proposed research, and state the total number of publications (e.g.,
30 of 40 total publications listed).
Funding information in NIH format
.
E.
Assurance Form
The principal investigator must complete the assurance form and sign it. The authorized grants administration officer must also sign and date the form.
A scan of the signed document, in pdf format, must be submitted as part of the proposal document.