Autologous hematopoietic stem cells in the treatment of geriatric patients with myeloma

Dr. Kouzi

Stem Cell Transplantation Viable Option in Geriatric Patients With Myeloma

JASON HARRIS

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.

Reference
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).

Leukemic clones in cord blood

Dr. Kouzi

PRELEUKEMIC CLONES AND THEIR IMPORTANCE TO TRANSPLANTATIONS

K. Koliakou MD, PhD Prof of Medicine

Medical Director of Biohellenika

Cancer as well as leukemia are manifested after a series of mutations which eventually result in carcinogenesis. The incidence of leukemia in children under the age of 15 is 1/2000, with the highest incidence occurring between 1-3 years. 81% of cases of leukemia in children are related to acute lymphoblastic leukemia (ALL) and from the rest of  the other forms,  the  more frequent is  Acute Myeloblastic Leukemia (AML). Although 85% of children with ALL have long-term survival, they still suffer from chronic morbidity and heart problems as complications of chemotherapy.
The probability of acute leukemia occurring in the first 15 years of an individual's life is 0.08%; 60% of children with ALL have recurrence after treatment and only 40% of them have long-term survival. Acute leukemia  in children is gradually established and is due to the concentration of two continuous mutations in the hematopoietic stem cells. This type of evolution is followed by ALL. The first mutation leads to the formation of pre-leukemic clones, which are not sufficient for the appearance of leukemia. A second mutation in the same cell population leads to the onset of ALL.

The agents implicated in the appearance of the second and determinant mutation are viral infections and common pathogens that lead the cell to failing to follow the normal cell cycle.  Four genes are responsible for the appearance of preleukaemic clones and their incidence is: TEL-AML1 (24-26%), E2A-PBX (5-6%), BCR-ABL (3-5%) and MLL- AF4 (5%). Pre-leukemic clones which are developed in  early stages of fetal’s life affect more cell lines and more dangerous they are to develop leukemia.
Some of these clones appear initially in the primitive mesenchymal cells of the umbilical cord tissue, from which the primitive hematopoietic cells are formed, which are then migrate to the hematopoietic organs. Pre-leukemic clones remain in the bloodstream and are detected even 15 years after birth. The most common gene detected in cord blood that is related to ALL is TEL-AML1 and its incidence in the newborn population is 1%. In fact, however, the occurrence of ALL  is 100 times lower, meaning that 1% of children with the TEL-AML1 mutation will eventually develop leukemia.
A significant number of healthy adults, according to some authors, the  42% and to others 74%,  carry a mutation of another leukemia gene, BCR-ABL, which are currently healthy. It seems that the presence of preleukemic clones is of little importance for the development of leukemia and a better marker is the number of hematopoietic cells bearing these mutations.
The earlier appearance of the first mutation to the  hematopoietic cell population  the more hematopoietic stem cells are affected that means higher risk of leukemia is occurred.  The  late mutations  occur in a particular hematopoietic cell population and a lower risk for the occurrence of leukemia exists. The frequency of pre-leukemic clones in the healthy monozygotic twin is ≈5%, and this is mainly due to the transfer of clones from one twin to the other through circulation rather than simultaneous leukemogenesis.
The surviving twin carries the pre-leukemic clone eight years after the death of the other twin and remains healthy. Umbilical cord blood has been used in recent years with increasing rates as a hematopoietic graft  for the treatment of malignant diseases. Since 1980, published  studies have been shown  that malignancy can be transferred through allogeneic haematopoietic grafts, and it has been found in 5% of recurrences of leukemia that is transplanted via the transplant after allogeneic bone marrow transplantation. This type of leukemia  is  not due to actual relapse of the initial leukemia,  but to new leukemia implanted through the transplant, Daniel Howard Wiseman (Biol Blood Marrow Transplant., 2011 Jun; 17 (6): 771-89).
Generally the transmitted malignancy through hematopoietic transplants ranges from 0.16% -5% and the mortality of patients from the use of these grafts is much greater. Pre leukemic  clones in umbilical cord blood are found at a frequency of up to 5%, or 1 in 20 children are born with pre-leukemic clones in their blood without any indication that all these infants will develop Acute Lymphoblastic Leukemia (ALL). 1% of pre-leukemic clones persisted in the hematopoietic stem cells and  result in leukemia. It is also unknown if all children with ALL had a pre-leukemic clone in the umbilical cord blood. Preleukemic clones gradually are removed from the blood by the immune system.
Pre-leukemic clones do not distinguish between public and private storage and occur at the same rate in both types of storage. Nowadays, the grafts are not examined for pre-leukemic clones in both Public and Private sector because the probability of progression to leukemia is very low and the social disruption would be too great, if examined. Public banks discretionary donor monitoring is recommended and not direct information on the resulting problem to the family.
In private storage grafts can be directly examined for the mutations and can be used safely if they do not have preleukemic  clones, especially in elder children.  Successful autologous umbilical cord blood stem cell transplantation in children with acute leukemia and hereditary cancers is reported in the literature.

The real reason that hematologists avoid to use autologous hematopoietic stem cells is not the fear of transplanted mutations, especially in the cases that they can check the transplant, but because  autologous  cord blood hematopoietic cells do not have the graft  versus leukemia effect  or antileukemic reaction.

Biohellenika successfully renewed the AABB accreditation

Dr. Kouzi

BIOHELLENIKA RENEWS THE INTERNATIONAL ACCREDITATION BY AABB

Today, September 7, 2018, Biohellenika is particularly proud to have successfully renewed its international accreditation by the American Association of Blood Banks (ΑΑΒΒ) after a two-day thorough inspection.  

Biohellenika's first accreditation took place in 2010 and has since been renewed every two years with success. This accreditation accepts the units that are kept in its laboratories in all hospitals in Greece and abroad. Accreditation by AABB is an internationally recognized guarantee of the quality of services offered by Biohellenika both for the processing and storage of units and for their release for therapeutic applications in clinics and hospitals in Greece and abroad. It should be noted that Biohellenika is the only Greek company that has successfully released units for treatment both in the United States and in Europe.

The president of Biohellenika SA, Dr. George Koliakos congratulates the staff of the company for their impeccable appearance during the AABB inspection conducted by a special assessor, lasted two days and said "It is very important for a Greek company to maintain the international accreditation during the hard years of the financial crisis.  With the international accreditation of AABB, the value and security of the services offered by the company to both the international medical society  and  parents who have chosen Biohellenika to preserve their children's stem cells is confirmed and guaranteed. The high-quality services of our company and the necessary infrastructures and investments required for this purpose are combined with a competitive pricing policy tailored to today's difficult economic conditions. Biohellenika remains faithful to its principles to serve proactive  parents who decide to secure the health of their children by keeping precious stem cells at birth ".

The unique services  that Biohellenika provides including collection of the umbilical cord blood, placenta perfusion, mesenchymal stem cells from the  entire umbilical cord, stem cells from the deciduous teeth, and adipose tissue, supplemented last year with the Very Small Embryonic Like Stem Cells (VSELs) from  the Umbilical Cord Blood and  Placenta Perfusion in combination with the latest generation of equipment, the state of the arts  laboratories, the  immediate service and the scientific and medical support  of the parents by distinguished doctors during the 20 years agreement,  highlight Biohellenika as a unique company that stands with humanity  and reliability to the needs of the families. The company also has a national accreditation from the ESYD and two certifications for its laboratories.

A few words about AABB
AABB is an international organization that accredits  institutions involved in cell therapies including transplantation medicine. It was founded in 1947 and is committed to promoting the improvement of health services by developing practices and standards in medical and cellular therapies to optimize the safety of both the donor and the patient. (www.aabb.org)

Very Small Embryonic Like Stem Cells (VSELs)

Dr. Koliakos

Biohellenika offers a new stem cell collection and storage service from cord blood, the VSELs, after a long-term effort by its Research and Development Department. Thus, the company overcomes the storage of whole cord blood, which aims to maintain VSELs, and offers the storage of VSELs as an independent service, ready for use.

The cord blood except the hematopoietic stem cells, contains another more primitive cell population, the second in hierarchy during evolution, that is named Very Small Embryonic Like Stem cells-VSELs). These cells are very small in size and because of that, using the conventional protocols they were lost during the hematopoietic collection. VSELs are suitable only for the child (autologous use) and this is one of the privileges that offers, among others, the private cord blood banking. From this cell population different cell lines were created in order to use for tissue and organ regeneration, in the case of their failure. Their presence in the cord blood gives new perspective in Regenerative Medicine beyond of hematology. Until now from VSELs created cardiomyocytes, lung covering epithelium, oocytes and sperm and in co culture with cord tissue mesenchymal stem cells they produce hematopoietic stem cells very useful in hematopoietic transplantations.

VSELs are a new stem cell population in the cord blood, but the most primitive, and may be is the missing puzzle in cellular therapies.