Treatment of Multiple Sclerosis with hematopoietic stem cells
- Dr. Kouzi
Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis A Randomized Clinical Trial
Richard K. Burt, MD1; Roumen Balabanov, MD2; Joachim Burman, MD3; et alBasil Sharrack, MD4; John A. Snowden, MD5; Maria Carolina Oliveira, MD6; Jan Fagius, MD3; John Rose, MD7; Flavia Nelson, MD8; Amilton Antunes Barreira, MD9; Kristina Carlson, MD10; Xiaoqiang Han, MD1; Daniela Moraes, MD6; Amy Morgan, APRN1; Kathleen Quigley, RN1; Kimberly Yaung, RN1; Regan Buckley, RN1; Carri Alldredge, RN1; Allison Clendenan, APRN1; Michelle A. Calvario, APRN1; Jacquelyn Henry, APRN1; Borko Jovanovic, PhD11; Irene B. Helenowski, PhD11
JAMA. 2019;321(2):165-174. doi:10.1001/jama.2018.18743
Question Is nonmyeloablative autologous hematopoietic stem cell transplantation (HSCT) more effective than disease-modifying therapy for patients with highly active relapsing-remitting multiple sclerosis (MS)?
Findings In this randomized clinical trial that included 110 patients with relapsing-remitting MS, treatment with nonmyeloablative HSCT compared with disease-modifying therapy resulted in a significantly prolonged time to disease progression (hazard ratio, 0.07).
Meaning In this preliminary study, nonmyeloablative HSCT was more effective than disease-modifying therapy for patients with relapsing-remitting MS.
Importance Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).
Objective To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.
Design, Setting, and Participants Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.
Interventions Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).
Main Outcomes and Measures The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.
Results Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, −1.7; 95% CI, −2.03 to −1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).
Conclusions and Relevance In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.
Trial Registration ClinicalTrials.gov Identifier: NCT00273364
Stem Cell Transplantation to Treat Multiple Sclerosis
Autologous hematopoietic stem cells in the treatment of geriatric patients with myeloma
- Dr. Kouzi
Stem Cell Transplantation Viable Option in Geriatric Patients With Myeloma
Patients with multiple myeloma who are older than 75 years could be viable candidates for autologous stem cell transplantation (ASCT).
A recent study of 604 patients with multiple myeloma who received ASCT at the John Theurer Cancer Center examined the overall survival (OS) and progression-free survival (PFS) rates in that population.
Forty-four of the patients were aged 75 to 84 years, and 560 were younger than 75 at the time of transplantation.
Results showed that the 3-year OS rate was 83.7% in the older cohort and 82.0% among younger patients. The median OS was 93.3 months and 127.8 months for the older and younger groups, respectively.
The 3-year PFS rate was 51.7% in the older group compared with 46.0% among younger patients. The median PFS was 36.1 months versus 33.7 months, respectively.
Older patients were also able to tolerate high-dose melphalan conditioning.
Andrew L. Pecora, MD, president of Physician Services and chief innovation officer at Hackensack Meridian Health, presented findings from the study at the 2018 ASCO Annual Meeting.
In an interview with OncLive®, a sister publication to Oncology Nursing News®, Pecora, who is also the chief innovation officer and vice president of Cancer Services at the John Theurer Cancer Center at Hackensack University Medical Center, discussed the use of ASCT in patients aged ≥75 years and the future of care in multiple myeloma.
Can you provide some background on your presentation?
ASCT has been proven in multiple phase III, prospective, randomized trials to improve survival among patients with multiple myeloma, whether it was done upfront after an induction regimen or done later at the time of progression. The real question was, “Were the data applicable to an older population?” Most of these trials were in a population younger than 65 years.
At John Theurer Cancer Center, where we have one of the largest myeloma transplant programs in the world, we're fortunate enough to have a database that allowed us to look at our patients at or older than 75 years and compare them with younger patients. What was really striking and important was that the data were nearly superimposable. The toxicities and the benefits were similar in the older age group versus the younger age group.
In addition to tolerating the toxicity, the principle concern that people have is that these are older stem cells. Are they going to engraft? Are they going to restore immunity? Or are they kind of tired? The answer is, “No.” The hematopoietic and immunologic reconstitution is just as brisk, as long as you give an adequate dose, as in a younger person.
Are there any comorbidities an older patient can have and still undergo ASCT?
If a patient has hypertension, diabetes, or a myocardial infarction but doesn't have residual damage to the heart, then transplantation would be acceptable. However, if patients have active comorbidities, such as unstable diabetes, low ejection fraction after a heart attack, a deficit after a stroke, or renal insufficiency as a result of lifelong hypertension, that would not be an appropriate population.
Do older patients typically want to undergo ASCT?
Age, in and of itself, does not define what a patient feels. I know a lot of 90-year-old patients who think they're young—and some of them live to be 105. You have to look at the patient. You have to, obviously, be certain a patient is articulating what they want—the outcome that matters most to them. If the patient is a “young” 75—still playing tennis, still working full-time, you have all your cognitive faculties, and you don't feel any different than when you were 65—we have proven that age, at least in ASCT for multiple myeloma, should not be a limiting factor.
Will ASCT continue to be the standard of care in multiple myeloma?
Transplant has been the steadiest thing in myeloma treatment over the past 15 years. With the advent of all the new drugs, first-generation immunomodulatory agents, monoclonal antibodies, proteasome inhibitors, and more, transplant is still there. It has still been shown that there is nothing that can provide, at least today, the benefit that a transplant can in a properly assessed patient.
That said, what is the future? There are new therapies coming down the pike, such as CD38-targeted chimeric antigen receptor (CAR) T cells. Maybe that will supplant transplant, but I don't know that we will be able to cure myeloma or get very deep remissions with the current medications we have without transplant. I don't know that in the future—even with CAR T cells or CAR natural killer cells with a CD38 construct—if they will be powerful enough to eradicate myeloma without the disease having been cytoreduced by ASCT. If I had to bet, I can't say 10 years, but 5 years from now we will still be doing transplants.
What are other updates related to transplant are you excited about?
We're still learning more and more about how haploidentical bone marrow transplant can be used. When I first learned immunology and learned that we were going to do half matches, I thought that was tantamount to homicide. I couldn't believe it. However, it really does work and it seems that it's equivalent to a matched unrelated donor. It's more ubiquitous because you don't need to find someone a match. You just need a family member who’s a half match. That's important.
The use of immunomodulators [is also interesting]. We now have follow-up data from a trial we presented in 2017 showing that you can use checkpoint inhibitors after transplant and they may improve outcomes. That is pretty exciting.
Dong N, McKiernan, Siegel DSD, et al. Autologous stem cell transplantation in multiple myeloma patients over age 75. J Clin Oncol. 2018;36(suppl; abstr 8025).