Back To: Home : Featured Technology : Stem Cell

CLICK HERE FOR WHAT'S NEW IN:
 

Guest Commentary: Improving results after hematopoietic stem cell transplantation
July 2018
by Karine Kleinhaus of Pluristem  |  Email the author
SHARING OPTIONS:

Improving results after hematopoietic stem cell transplantation
 
By Dr. Karine Kleinhaus of Pluristem Therapeutics
 
Hematopoietic stem cell transplantation (HSCT) is a broad term that covers the transplantation of blood progenitor/stem cells from any source. It has become a powerful tool to treat numerous conditions. Indeed, physicians perform more than 50,000 first HSCTs annually; of these, 53 percent are autologous (taken from the patient) and 47 percent are allogenic (taken from a donor other than the patient).
 
Among the conditions HSCT can treat are: acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, myelodysplastic syndromes, multiple myeloma, non-Hodgkin lymphoma, Hodgkin disease, aplastic anemia and pure red-cell aplasia—but this list is not exhaustive.
 
HSCT has four possible outcomes: failure (when the transplanted cells just don’t take, a rare result); partial success (commonly called incomplete engraftment, when the cells are living inside the patient’s bone, but they are not active enough to keep the patient transfusion-independent); success with complications (when the cells are active enough to make the patient transfusion-independent but other health issues arise); and success without complications. In the first case, a second transplant is possible or other therapies can be considered, but the prognosis is usually disheartening.
 
Incomplete engraftment
 
Incomplete engraftment (poor graft function) requires the patient to undergo more transfusions of red cells or platelets. There are complications of serial transfusions of either of these cell types, and a patient needs intense prophylactic treatments to protect from infections if his or her white counts are low. The current treatment for incomplete hematopoietic recovery includes administration of factors stimulating white and red blood cell growth, such as granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin.
 
However, a significant number of patients do not respond to growth factors and may continue to require frequent transfusions, which expose them to transfusion-related risks such as allo-sensitization and infections, without providing a definitive cure. Regular transfusions are also associated with significant costs. Thus, there is an unmet need for additional treatment options for these patients.
 
Several groups are conducting trials to determine whether cellular therapy could be the treatment of choice for poor graft function after HSCT. Pluristem Therapeutics, based in Haifa, Israel, is currently recruiting patients in the United States and Israel for its Phase 1 trial of PLX-R18 cells in this unmet need. PLX-R18 cells, derived from mesenchymal-like cells collected from donated placentas, are designed to release a combination of therapeutic proteins to jumpstart the regeneration of a poorly functioning hematopoietic system. The cells are also being evaluated in a variety of other hematologic indications.
 
Other groups are also working on cell therapies for the treatment of poor graft function after HSCT. These include a group of researchers from multiple academic institutions in Belgium, headed by Yves Beguin from the University Hospital of Liege. Their ongoing Phase 2 study is evaluating whether infusion of mesenchymal stem cells (MSCs) can treat steroid-resistant acute graft-versus-host disease (GVHD) or poor graft function after HSCT. The study is expected to be completed in December 2019. Researchers from several academic institutions in China—headed by Qifa Liu, of the Nanfang Hospital of Southern Medical University—are also studying MSCs as a therapy for poor graft function. One trial is testing whether MSCs with or without peripheral blood stem cells could treat poor graft function and delayed platelet engraftment. In another trial, this group is evaluating whether peripheral blood stem cells combined with MSCs can treat poor graft function.
 
Side effects of HSCT
 
Even when successful, HSCT can have some potentially dangerous side effects. Infections are quite common, though antibiotic treatments are usually successful. Organ damage and, among female patients, infertility are more difficult to address but can be managed in some cases. GVHD, which is common among allogenic HSCT and rare in autologous HSCT, can be acute or chronic. This complication can be lethal and is often very difficult to treat.
 
GVHD
 
GVHD develops when the donor’s immune cells mistakenly attack the patient’s normal cells. GVHD can be mild, moderate or severe—even life-threatening. An ounce of prevention is always worth a pound of cure, so patients usually receive a regimen of preventative immune suppressors a day or two before their infusion. The regimen may include: Cyclosporine and methotrexate, Tacrolimus (Prograf) and methotrexate, Tacrolimus and mycophenolate mofetil (CellCept) as well as Prograf and sirolimus (Rapamune).
 
However, GVHD still happens, and it comes in two varieties, acute and chronic. Acute GVHD usually manifests within 100 days following HSCT. It is induced by donor T cells responding to the mismatched host polymorphic histocompatibility antigens. Chronic GVHD generally manifests later (>100 days) and has some features of autoimmune diseases. It may develop either de novo or following resolution of—or as an extension of—acute GVHD.
 
Acute GVHD
 
Treating aGVHD can take many forms. Topical corticosteroids (e.g., triamcinolone 0.1%) have proven effective for some skin aGVHD. Often, physicians will continue the original immunosuppressive prophylaxis (cyclosporine or tacrolimus [FK506]) while adding methylprednisolone.
 
Additional therapies, which can be used alone or in combination, include: anti-CD5-specific immunotoxin, anti-interleukin-2 (IL-2) receptor, ATG, mycophenolate mofetil, sirolimus and XomaZyme (a pan T-Cell ricin A-chain immunotoxin). There is no data from a well-conducted controlled trial showing that any of these is more effective than any other.
 
If these initial therapies fail, secondary therapies include ATG or multiple pulses of methylprednisolone Sirolimus, Infliximab, Etanercept, Mycophenolate mofetil (MMF) and Ruxolitinab, among others.
 
In August 2017, the FDA expanded the approval of Imbruvica (ibrutinib) for the treatment of adult patients with chronic GVHD (cGVHD) after failure of one or more treatments. This is the first FDA-approved therapy for the treatment of cGVHD. Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, was quoted in the announcement by the FDA as saying, “Patients with cGVHD who do not respond to other forms of therapy—typically corticosteroids to suppress their immune system—now have a treatment option specifically indicated to treat their condition.” Imbruvica, a kinase inhibitor, was previously approved for treating certain chronic lymphocytic leukemias, Waldenström’s macroglobulinemia and marginal zone lymphoma. It is under accelerated approval status for mantle cell lymphoma.
 
However, some aGVHD is steroid refractory. Currently, there are no approved therapies for patients with steroid-refractory aGVHD in the United States, and off-label options have demonstrated mixed efficacy. These include mycophenolate mofetil (MMF), etanercept, photopheresis, mesenchymal stromal cells, sirolimus and pentostatin. Other agents that can be tried include monoclonal antibodies directed against such targets as CD25, TNF-alpha, the T cell receptor, and the IL-2 receptor. There are limited data to guide the choice of therapy. Mesoblast is developing MSC-100-IV to treat these cases, and it has demonstrated immunomodulatory properties to regulate T cell-mediated inflammatory responses by inhibiting T cell proliferation and down-regulating the production of the pro-inflammatory cytokines, including tumor necrosis factor-alpha, or TNF-alpha, and interferon gamma.
 
Chronic GVHD
 
Although the clinical presentation of cGVHD mostly resembles scleroderma, it can mimic any other autoimmune disease. Immunosuppression with corticosteroids, tacrolimus and mycophenolate mofetil are the mainstays of treatment. Hydroxychloroquine, an antimalarial drug, is effective in several autoimmune disorders, including cGVHD. A major cause of death in cGVHD is infection from profound immunodeficiency associated with the disease. All patients require prophylaxis against encapsulated organisms, and patients with frequent infections and low immunoglobulin levels should receive intravenous immunoglobulin replacement.
 
Mary E.D. Flowers and Paul J. Martin noted in Blood, “Management of chronic GVHD has relied on corticosteroids as the mainstay of treatment of >3 decades … Prolonged systemic corticosteroid treatment causes significant toxicity, including weight gain, bone loss, myopathy, diabetes, hypertension, mood swings, cataract formation and increased risk of infection.”
 
Approximately 50 to 60 percent of cGVHD patients who undergo systemic treatment require a secondary treatment within two years of their initial treatment. “No consensus has been reached regarding the optimal choice of agents for secondary treatment of chronic GVHD, and the published literature provides little useful guidance.” Physicians generally use ECP, Rituximab, Imatinib, Pentostatin, mesenchymal stem cells, mycophenolate mofetil, mTOR inhibitor and Interleukin-2—and again, this list is not exhaustive.
 
As with the acute variety, some cGVHD is steroid refractory. Research into treatments again includes Pluristem’s PLX-PAD cell therapy. Last November, the company signed an agreement with Tel Aviv Sourasky Medical Center (Ichilov Hospital) to conduct a Phase 1/2 trial.
 
Conclusion
 
HSCT represents a revolution in the treatment of many maladies, but it is an incomplete revolution at present. Treatments of incomplete engraftment as well as acute and chronic GVHD are advancing but our understanding of the causes is far from complete. Studies to improve treatment are underway. However, our ability to prevent or quickly and easily remedy these health issues remains over the horizon.

Karine Kleinhaus, M.D., M.P.H., is divisional vice president, North America at Pluristem Therapeutics.

Back


PAGE UTILITIES


CONTACT US
DDNEWS
Published by Old River Publications LLC
19035 Old Detroit Road
Rocky River, OH USA 44116
Ph: 440-331-6600  |  Fax: 440-331-7563
 
© Copyright 2018 Old River Publications LLC. All righs reserved.  |  Web site managed and designed by OffWhite.