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State of the science: High-priority transplant trials for nonmalignant disease
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Last June, we launched a series of columns in HemOnc Today intended to discuss high-priority proposals that emerged from the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium.
The State of the Science Symposium (SOSS), which started in 2001 and is held every 7 years, highlights the challenges and research priorities facing hematopoietic cell transplantation.
Several topic-specific committees composed of scientific and clinical leaders in the field of stem cell transplantation were formed to identify the most compelling opportunities for clinical research and to frame the scientific agenda going forward for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in the next several years. Ten topic-specific committees identified 12 key study concepts.
Hemant Murthy
William Wood
Each of our columns discussing these proposals begins with a clinical scenario that highlights one or more high-priority concept areas in a way that is intended to be applicable to the nontransplant clinician. We then provide scientific background in that area and discuss specific high-priority concept strategies proposed by the SOSS committee in this area. Each column concludes with some thoughts on the potential impact these strategies may have for nontransplant providers.
In this column, we discuss a unique transplant indication, as we discuss the SOSS priorities related to nonmalignant disease.
Clinical scenario
Your neurologist colleague tells you about a patient he is treating, a 35-year-old woman was diagnosed with multiple sclerosis (MS) 2 years ago.
Although she is fairly functional, she walks with a gait disturbance and has some mild visual impairment. Numerous relapses have plagued her, which have caused slurring of her speech, severe muscle spasms and loss of sensation in her arms. These symptoms have resolved each time, but the flares recently have become more severe and have become more frequent in the last year.
She has been treated for the last 18 months with interferon, but it has done little to limit the frequency of relapses. Your colleague is now considering other second-line agents for treatment, such as natalizumab (Tysabri, Biogen), and he asks you about the potential role of stem cell transplantation.
MS and ASCT
MS is an autoimmune disease that results in central nervous system demyelination and axonal damage. It typically presents as a series of relapses and remissions owing to episodic activation of the immune system and subsequent repair.
More than 80% of individuals with MS experience a relapsing-remitting disease course. Relapsing-remitting MS is characterized by clearly defined attacks of worsening neurologic function followed by partial or complete remission periods. However, the accumulation of central nervous system damage and neurologic disabilities with little to no evidence of remission can characterize a progression to a secondary progressive MS (SP-MS). Approximately 10 years after disease onset, an estimated 50% of individuals with relapsing-remitting MS (RR-MS) will have converted to SP-MS.
MS treatments have targeted inflammation reduction as a way to decrease the frequency of relapses and slow the progression to SP-MS while improving quality of life, which is otherwise often impaired in early RR-MS. These therapies have ranged from first-generation disease-modifying therapies such as interferon-beta and glatiramer acetate, to immunosuppressive therapies such as mitoxantrone (also approved for treatment of SP-MS), to antibody-based therapies such as alemtuzumab (Lemtrada, Genzyme), natalizumab, rituximab (Rituxan; Genentech, Biogen Idec) and ocrelizumab (Genentech and Biogen Idec).
Oral disease-modifying therapy agents such as fingolimod (Gilenya, Novartis), teriflunomide (Aubagio, Genzyme/Sanofi) and dimethyl fumarate (Tecfidera, Biogen) also are available. To date, there are 10 FDA-approved therapies for treatment of RR-MS.
Autologous stem cell transplantation (ASCT) has benefited patients with autoimmune disorders in the past, often in the context of treating patients with primary hematological illnesses and comorbid autoimmune conditions. Buoyed by preclinical data that show the potential benefits of transplant in autoimmune diseases, cooperative groups such as the European Society for Blood and Marrow Transplantation (EBMT) working party for autoimmune disorders began to study transplant for these indications a few decades ago.
In 1997, Fassas and colleagues reported the first pilot phase 1/phase 2 study of ASCT with BEAM (which consists of carmustine, etoposide, cytarabine and melphalan) plus anti–T-lymphocyte globulin (ATG) conditioning for MS. Results showed durable neurologic improvement in more than 50% of severely disabled patients studied.
Since that time, more than 600 bone marrow-based transplants for the treatment of MS have been reported in the literature.
A combined Center for International Blood and Marrow Transplant Research and EBMT registry study reviewed 281 patients from 23 centers in 13 countries who underwent transplant between 1995 and 2006. Median follow-up was 6.6 years.
Results showed a 49% probability of 5-year PFS and 93% probability of 5-year OS. Factors associated with greater risk for MS progression included age older than 37 years, more than two prior MS treatments, and progressive vs. RR-MS.
A 3-year interim analysis of the HALT-MS study recently was published. HALT-MS was a phase 2, multicenter trial of ASCT with BEAM plus ATG conditioning for relapsing-remitting MS.
Patients who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrollment were eligible. Thus far, 24 patients on study have received ASCT.
At 3 years, EFS was 78.4% and PFS was 90.9%. There was overall improvement from baseline in neurologic function as measured by the Expanded Disability Status Scale (EDSS) in each year post-ASCT, and improvement in quality of life as measured by the nine-item MS Impact Scale (MSIS-29). Reduction of gadolinium lesions was noted immediately after transplant, and no new gadolinium-enhancing lesions were reported at 3 years post-ASCT. Five patients (21%) failed according to primary endpoint criteria, which was increase in expanded disability status scale score or clinical relapse.
Most adverse effects were ASCT-related and expected. They included grade 3 or grade 4 hematopoietic and gastrointestinal toxicities. Other notable toxicities reported included two suicide attempts late after transplant and two deaths, one from MS progression and the other from complications of asthma.
High-priority strategies
There currently are no accepted guidelines for when to perform ASCT for MS. It also is unclear whether transplant is superior to newer anti-inflammatory therapies in the treatment of this disease.
The BMT SOSS strategy is to define the role of ASCT in the treatment of MS.
The BMT SOSS adult nonmalignant disease committee proposed a definitive randomized trial to test whether myeloablative conditioning followed by ASCT will result in better outcomes than best available therapy.
In the concept presented, eligibility criteria would include age 18 to 45 years; highly active, RR-MS diagnosed within the past 5 years; failure of at least one conventional disease-modifying drug; and ability to receive additional disease-modifying therapy. Eligible patients also would have an EDSS score between 2.5 and 5.5. These scores range from mild disability in one functional system to ambulation restricted to about 100 meters and disability severe enough to preclude full daily activities.
Three-year inflammatory DFS — defined as absence of clinical relapses, gadolinium-enhancing lesions and new T2 lesions on MRI — would serve as the primary endpoint. Secondary endpoints would include freedom from sustained accumulation of disability, sustained improvement in disability, and quality-of-life and health economic analyses.
Planned enrollment would be approximately 120 patients, with 60 patients per treatment arm. This is thought to be required to detect absolute improvement in DFS from 60% to 80%, which would keep in line with the 65% 2-year RFS in alemtuzumab-treated patients in the CARE-MS II trial for patients with MS who failed first-line therapy, or the 67% 2-year RFS in natalizumab-treated patients in the AFFIRM trial. An extension study would examine 5- to 7-year freedom from sustained accumulation of disability and responses to subsequent treatment for patients who fail the study treatment.
Patient recruitment could be an issue, highlighting the importance of developing a referral network whereby patients with MS would be referred to a limited number of study centers with expertise in both MS and stem cell transplantation.
Conclusion
MS remains a debilitating and disabling condition. Many therapies target inflammation reduction to halt progression of MS and to improve quality of life.
ASCT for RR-MS has shown benefit in small studies with regard to controlling relapses when other therapeutics have failed, halting progression to SP-MS in a subset of patients, and improving recovery from longstanding disabilities.
The question remains whether autologous transplantation is better than currently available disease-modifying therapies, as well as where it would fit best in a treatment algorithm for RR-MS.
For the patient in our initial vignette, enrollment on a study of ASCT could be a reasonable strategy — either now or if she were to fail a second-line treatment — provided that she meets the outlined entry criteria.
As always, we welcome further conversation or questions about these topics. Readers are encouraged to email us at wawood@med.unc.edu or comment on this column at Healio.com/HemOnc so we can continue this dialogue.
References:
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Atkins HL and Freedman MS. Neurotherapeutics. 2013;doi:10.1007/s13311-012-0162-5.
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Bowen JD, et al. Bone Marrow Transplant. 2012;doi:10.1038/bmt.2011.208.
Coles AJ, et al. Lancet. 2012;doi:10.1016/S0140-6736(12)61768-1.
Fassas A and Kazis A. J Hematother Stem Cell Res. 2003;12:701-711.
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Fassas A, et al. Bone Marrow Transplant. 1997;20:631-638.
Nash RA, et al. JAMA Neurol. 2015;doi:10.1001/jamaneurol.2014.3780.
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Radaelli M, et al. Curr Neurol Neurosci Rep. 2014;doi:10.1007/s11910-014-0478-0.
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For more information:
Hemant Murthy, MD, is a hematology-oncology fellow at East Carolina University — Brody School of Medicine in Greenville, N.C.
William Wood, MD, is an assistant professor of medicine in the division of hematology/oncology at the University of North Carolina in Chapel Hill. He also is a HemOnc Today Editorial Board member. He can be reached at UNC Health Care System, Division of Hematology and Oncology, 101 Manning Drive, Chapel Hill, NC 27514; email: wawood@med.unc.edu. You also may follow him on Twitter (@WoodBD).
Disclosure: Murthy and Wood report no relevant financial disclosures.