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BLOG: The Role Of Haploidentical Bone Marrow Transplant For Severe Aplastic Anemia
March 31, 2025
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Key takeaways:Immunosuppressive therapy improves pancytopenia in severe aplastic anemia.
However, its effects are not long-lasting as evidenced by a modest 2-year EFS rate of just 46%, prompting the need for alternative donor hematopoietic (bone marrow) cell transplantation (BMT) for most patients without matched donors.
Advances in preventing graft-versus host disease and the availability of haploidentical donors could transform aplastic anemia.
The BMT CTN 1502 trial marked a significant step forward in severe aplastic anemia treatment. This trial successfully used haploidentical BMT for 31 patients — both children and adults — with a reduced-intensity conditioning regimen along with post-transplantation cyclophosphamide-based GVHD prophylaxis.
Because this trial offered an alternative BMT for patients without fully matched unrelated donors, over 60% of the participants came from underrepresented racial and ethnic communities.
After 1 year, 24 patients were alive and engrafted. The patients experienced low incidence of GVHD, with no instances of severe chronic GVHD reported.
This innovative study expands the range of donor options and enhances access to BMT for various demographic groups.
Following this, researchers at Johns Hopkins established BMT as a first-line treatment in a phase 2 study that involved 27 patients newly diagnosed with severe aplastic anemia using a conditioning regimen that included rabbit anti-thymocyte globulin (ATG), fludarabine, cyclophosphamide and a total body irradiation conditioning of 2 Gy to 4 Gy. The participants' median age was 25 years, with over 35% from underrepresented backgrounds.
Among the first seven patients who received lower total body irradiation doses (2 Gy), the graft failure rate notably was high (n = 3 of 7). The subsequent 20 patients received 4 Gy total body irradiation as part of conditioning, and no patients experienced graft failure.
The 3-year OS rate was an impressive 92% for the entire cohort, with the 4 Gy TBI group achieving a remarkable 100% survival rate and no treatment-related mortalities.
By 1 year, 89% of patients had graft failure-free survival, with 24 patients exhibiting over 95% donor chimerism.
These results are encouraging, especially considering that half of these patients had very severe aplastic anemia, where early mortality associated with immunosuppressive therapy is considerable due to extended neutropenia. Remarkably, the cumulative incidence of grade I or grade II acute GVHD on day +100 was 7%, and mild chronic GVHD at 2 years was 4%. No patient had grade III or grade IV acute GVHD or moderate/severe chronic GVHD.
These findings suggest that haploidentical cell transplant could be considered as a feasible treatment option in the upfront setting for suitable patients with aplastic anemia when no HLA-matched related or unrelated donor is available.
Two randomized BMT CTN trials are in progress.
The phase 3 TransIT trial aims to determine whether allogeneic BMT with unrelated donors enhances survival rates for young patients with severe aplastic anemia compared with immunosuppressive therapy. The phase 2 CureAA trial will investigate GVHD failure-free survival rates among adults with aplastic anemia receiving haploidentical vs. Unrelated donor BMT.
Both studies have the potential to significantly change clinical practice, encouraging the use of alternative donor transplants as frontline treatment for newly diagnosed severe aplastic anemia.
References:For more information:Phuong T. Vo, MD, is associate professor in the clinical research division at Fred Hutch Cancer Center. Vo can be reached at ptvo@fredhutch.Org.
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National Anaemia Day: When Should Anaemia Patients Consider A Bone Marrow Transplant?
Anaemia remains a major public health concern in India, affecting women, children and pregnant mothers, leading to severe health complications. Firstpost brings you an expert's view on when a transplant becomes necessary and the risks associated with the procedure read more
Anaemia remains a pressing public health issue in India mainly due to iron deficiency which hampers cognitive and motor development in children and reduces work capacity in adults.
Pregnant women with anaemia face increased risks of complications such as perinatal loss, prematurity and low birth weight infants. While dietary adjustments and supplements can help manage mild to moderate cases, severe forms of anaemia may require advanced treatments including a bone marrow transplant (BMT).
Firstpost spoke to Dr Rahul Bhargava, the principal director and chief BMT, Fortis Memorial Research Institute, Gurugram, to explain various aspects of the disease.
Anaemia and role of bone marrow transplantsAnaemia is a common disorder characterised by insufficient production or dysfunctional red blood cells. While many cases can be addressed through lifestyle changes, dietary modifications, supplements, or medication, severe forms may necessitate more advanced treatments, says Dr Bhargava.
In certain situations, a bone marrow transplant (BMT) may be the best or only option. However, determining when to consider BMT depends on the underlying cause and severity of the condition, he said.
Conditions that may require BMTBone marrow transplants are typically reserved for individuals with severe, life-threatening conditions that impair the bone marrow's ability to produce healthy blood cells. Key conditions include:
Aplastic Anaemia: It is a rare disorder where the bone marrow fails to produce enough blood cells, leading to extreme fatigue, frequent infections, and uncontrolled bleeding. If traditional treatments like immunosuppressive therapy or blood transfusions fail, BMT may be necessary.
Sickle Cell Anaemia: A genetic disorder causing misshapen and sticky red blood cells, leading to blood vessel blockages, severe pain, and organ damage. While medications and transfusions can manage symptoms, BMT is the only known cure, often recommended for children or young adults with severe complications.
Thalassemia Major: An inherited condition causing defective hemoglobin production, leading to severe anaemia and requiring regular blood transfusions. Over time, transfusions can cause iron overload and organ damage. BMT, ideally performed at a young age, can offer a permanent cure.
Myelodysplastic Syndromes (MDS): A group of disorders where the bone marrow produces abnormal blood cells, which can progress to leukaemia. For high-risk MDS patients unresponsive to other treatments, BMT may be the best option to prevent disease progression.
Risks, considerations and way forwardThe decision to undergo a bone marrow transplant depends on several factors, including the severity of the condition, the patient's overall health, the availability of a suitable donor, and potential risks.
The procedure involves high-dose chemotherapy or radiation to destroy the diseased bone marrow, followed by the transplantation of healthy stem cells from a donor. While BMT can be life-saving, it carries significant risks, such as infections, graft-versus-host disease (GVHD), and complications from pre-transplant treatments, Dr Bhargava said.
Ultimately, the decision to pursue BMT should be made in consultation with a haematologist or transplant specialist, who will evaluate the risks and benefits based on the patient's medical history and the progression of their anaemia, he said.
For individuals with severe, treatment-resistant anaemia caused by conditions like aplastic anemia, sickle cell disease, or thalassemia, BMT offers hope for a healthier future, Dr Bhargava said.
End of Article
Orca-T Doubles Graft-Versus-Host Disease-Free Survival In Leukemia
Treatment with the T-cell immunotherapy Orca-T improved survival free of moderate-to-severe chronic graft-versus-host disease across leukemia subtypes.
Orca-T improved survival free of moderate-to-severe cGVHD across leukemia subtypes: © nobeastsofierce - stock.Adobe.Com.
Orca-T, a T-cell immunotherapy, significantly improved survival free of moderate-to-severe chronic graft-versus-host disease (cGvHD) compared with allogeneic hematopoietic stem cell transplant (alloHSCT) in the phase 3 Precision-T study for patients with acute myeloid leukemia, acute lymphoblastic leukemia, high-risk myelodysplastic syndrome and mixed-phenotype acute leukemia, according to a news release from the drug's manufacturer, Orca Bio.
After a median follow-up time of 11.4 months, the primary end point of survival free of cGvHD was 78% in those who received Orca-T (93 patients) and 38% in those who received alloHSCT (94 patients). An interim analysis of the secondary end point of overall survival showed rates of 94% with Orca-T arm and 83% with alloHSCT. An additional secondary end point, the cumulative incidence of moderate-to-severe cGvHD, was 13% with Orca-T arm versus 44% with alloHSCT.
Glossary:Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT): a procedure where a patient receives stem cells from a donor to replace their bone marrow.
Graft-versus-Host Disease (GvHD): a condition that can occur after a stem cell or bone marrow transplant when the transplanted cells attack the recipient's body tissues.
Moderate-to-Severe Chronic GvHD (cGvHD): a prolonged form of GvHD that can cause long-term symptoms, such as skin rashes, liver problems and digestive issues.
Non-Relapse Mortality: death occurring in patients due to causes other than the return of the original cancer, such as infection or organ failure, after a transplant.
Overall Survival: the length of time from the start of treatment until death from any cause.
At one year, exploratory endpoints showed a relapse-free survival rate of 76% in the Orca-T arm and 74% in the alloHSCT arm. The cumulative incidence of non-relapse mortality was 3% in the Orca-T arm and 13% in the alloHSCT arm. Additionally, the cumulative incidence of grade 3 (severe) or 4 (life-threatening) acute GvHD was 6% in the Orca-T arm and 17% in the alloHSCT arm.
No new safety concerns were identified with Orca-T. Grade 4 or higher infections occurred in 6% of patients in the Orca-T arm and 10% in the alloHSCT arm.
"The Precision-T study showed double the rate of survival free from GvHD with Orca-T versus a conventional transplant, a relapse-free survival rate of 76% and no new safety concerns," Dr. Everett Meyer said in the release. "These findings are highly encouraging and provide compelling new evidence as we work to solve for the critical factors contributing to the needs of this patient population."
Meyer, the presenting author of this study, is a hematologist and associate professor of medicine in Blood and Marrow Transplantation and Cellular Therapy at Stanford Health Care.
The complete results will be presented April 2, 2025, at the 51st Annual Meeting of the European Society for Blood and Marrow Transplants (EBMT) in Florence, Italy.
Orca-T, an investigational allogeneic T-cell immunotherapy, consists of highly purified regulatory T-cells, CD34+ stem cells and conventional T-cells from peripheral blood of related or unrelated matched donors. The U.S. Food and Drug Administration (FDA) has granted Orca-T regenerative medicine advanced therapy and orphan drug designation for preventing GVHD or death in patients eligible for hematopoietic stem cell transplant.
According to an article from the Cleveland Clinic, GvHD is a complication that may arise following treatment with alloHSCT, where you receive blood-forming stem cells from a donor. This transplant is often used to treat blood cancers like leukemia or lymphoma and bone marrow diseases like aplastic anemia. In GvHD, the donor's cells see your body's cells as a threat and attack them, leading to complications.
Regenerative medicine advanced therapy designation is granted to a drug that is a regenerative medicine therapy, such as cell therapy, tissue engineering product, or human cell and tissue product, intended to treat or cure a serious disease, according to the official FDA website, fda.Gov. Furthermore, according to the regulatory website, orphan drug designation is a status granted by the U.S. FDA to drugs and biologics intended to treat rare diseases or conditions.
Precision-T is a randomized, open-label, multi-center study evaluating the safety, efficacy, and tolerability of Orca Bio's investigational allogeneic T-cell immunotherapy, Orca-T, compared to conventional alloHSCT. The study received guidance from the U.S. FDA and involved patients with acute myeloid leukemia, acute lymphoblastic leukemia, high-risk myelodysplastic syndrome and mixed-phenotype acute leukemia. Nineteen leading treatment centers across the U.S. Enrolled 187 patients in the trial.
"Approximately 46,000 people are diagnosed with [acute myeloid leukemia, acute lymphoblastic leukemia and high-risk myelodysplastic syndrome] in the U.S. Each year, but only a fraction of them receive an allogeneic stem cell transplant within the current paradigm," Dr. Rawan Faramand, Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, said in the news release. "Additional treatment options are needed, and the introduction of a cell therapy like Orca-T that leverages a precision-based approach could pave the way for a new standard of care for patients with various hematologic malignancies."
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