HAPLO2019: Advances in Haploidentical Transplantation and Other Novel Cellular Therapies

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Now in its seventh year, the Haploidentical Transplant Symposium (HAPLO) continues to explore advances in haploidentical and other novel cellular therapies. The most recent of these meetings—HAPLO2019—met in Orlando, Florida, 2 days before the start of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition. A summary of important aspects presented at the meeting are summarized below.

Getting Patients to Transplant Sooner May Improve Outcomes

“More than seven recent studies investigating haploidentical transplants for sickle cell disease showed high event-free survival and low rates of severe graft-vs-host disease and mortality.”
— Stefan Ciurea, MD

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Stefan Ciurea, MD, Associate Professor of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center in Houston, and Program Chair for HAPLO2019, reviewed the evidence for getting patients to transplant faster and new data related to transplantation for sickle cell disease.

The development of haploidentical transplantation has been a major step forward in extending transplantation to a great majority of patients in need, with outcomes similar to human leukocyte antigen (HLA)-matched unrelated donors. Another major benefit might be to be able to proceed quicker to transplantation, as the median time to obtaining an unrelated donor graft is approximately 3 months.

According to Dr. Ciurea, faster transplantation with haploidentical donors, which can be performed in approximately 2 to 3 weeks, could be especially important for patients with either more advanced disease or persistent detectable disease by any of the methods currently in use, including the detection of minimal residual disease (MRD) by flow cytometry, cytogenetics, and molecular methods.

“The hypothesis is that proceeding to transplantation quickly will allow more patients to have access to transplant, but the question remains as to whether that will improve outcomes,” Dr. Ciurea said.

In a single-center study at MD Anderson, patients with acute myeloid leukemia (AML) who had detectable MRD and underwent urgent haploidentical stem cell transplant, had the same outcomes as in those patients with undetectable MRD. Older patients tended to benefit less compared with younger patients, likely due to the use of lower-intensity conditioning regimens and because disease in older patients tends to be more high risk.1

“These results are in sharp contrast with results reported in which MRD-positive patients in complete remission had relapse rates in excess of 60% to 70% and poor disease-free survival,”2 Dr. Ciurea commented. “Interestingly, 67.2% of these patients received an unrelated donor transplant, suggesting that time to transplantation might be important.”

A separate study looked at patients with HLA-matched unrelated donors and compared them with patients who started a matched unrelated donor search. The investigators found that those who received haploidentical transplants had a 25% better survival compared with those who received matched unrelated donor transplants, although the difference was not statistically significant, probably due to the small number of patients included in this study.3

“However, this study clearly showed that outcomes are not compromised by proceeding faster to transplantation with haploidentical donors when a reduced-intensity, melphalan-based conditioning was employed,” Dr. Ciurea noted.

“These findings suggest that if we can get patients to transplant sooner with haploidentical donors, we might be able to favorably influence outcomes for those patients who need to get to transplantation as soon as possible using this approach,” Dr. Ciurea commented.

A larger, multicenter, observational study under the sponsorship of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is evaluating whether proceeding to transplant faster using haploidentical donors will improve treatment outcomes in adults and children with acute leukemia, myelodysplastic syndromes, lymphomas, and some nonmalignant diseases ( identifier NCT03904134).

In an interview with The ASCO Post, Syed Ali Abutalib, MD, a regular attendee of these meetings, commented: “Before results of this trial are available, the current standard in the transplant community remains HLA-matched sibling donor as the first choice, followed by HLA-matched unrelated donor, and in cases when such grafts are unavailable, it is reasonable to pursue an HLA-mismatched donor, ie, an HLA-haploidentical graft.” Dr. Abultalib is Associate Director of the Hematology and Bone Marrow Transplantation Program and Director of the Clinical Apheresis Program at Cancer Treatment Centers of America in Chicago; Associate Professor at Roseland Franklin University of Medicine and Science; as well as Founder and Co-Editor of Advances in Cell and Gene Therapy.

“The logistics involved in manufacturing and treating with autologous CAR T cells adds a layer of complexity, which can be more efficiently managed with therapeutically successful ‘off-the-shelf’ CAR T cells.”
— Syed Ali Abutalib, MD

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Emerging Role of Haploidentical Transplant for Sickle Cell Disease

“Extending transplantation for patients with severe, congenital hemoglobinopathies, such as sickle cell disease, is a very important topic because it is primarily a disease affecting a minority population who are mostly without HLA-matched donors. Consequently, until recently, transplantation was performed only with HLA-matched sibling donors, and patients without such donors were not considered for transplant,” Dr. Ciurea explained.

“Patients with sickle cell disease experience extensive morbidity and early mortality. Allogeneic hematopoietic stem cell transplantation offers a chance to cure their disease. Courtney Fitzhugh, MD, and colleagues from the National Institutes of Health have been interested in transplanting patients with sickle cell disease, more recently using haploidentical donors with very good results, as presented at HAPLO2019,” Dr. Ciurea explained.4

“These authors used a reduced-intensity conditioning regimen. Their findings, in addition to the recently reported experience from Johns Hopkins,5 suggest that a reduced-intensity conditioning regimen that induced high donor chimerism and effective posttransplant cyclophosphamide–based graft-vs-host disease prophylaxis is sufficient to cure the vast majority of patients with this disease,” he continued.

Courtney Fitzhugh, MD

Courtney Fitzhugh, MD

“In fact, more than seven recent studies investigating haploidentical transplants for sickle cell disease showed high event-free survival and low rates of severe graft-vs-host disease and mortality,” Dr. Ciurea commented.

BMT CTN 1507 is also investigating, in a multicenter study, the use of haploidentical donor transplants for sickle cell disease. “Results are eagerly awaited,” he said.

“I believe that we can now safely use haploidentical donors for transplantation for sickle cell disease with excellent results. This is another major step forward for extending transplantation to a group of patients who otherwise would have had a shorter and very difficult life span,” Dr. Ciurea said.

Dr. Abutalib commented: “Once proved successful across major trials, such an approach could significantly improve outcomes of many adults with sickle cell disease and broaden their therapeutic choices. However, nonmedical barriers must be addressed so more patients with this disease can be potentially cured.”

Update on CAR T-Cell Therapy

Miguel-Angel Perales, MD, provided an update on chimeric antigen receptor (CAR) T-cell therapy. Dr. Perales is Deputy Chief of the Adult Bone Marrow Transplant Service and Director of the Adult Bone Marrow Transplantation Fellowship Program at Memorial Sloan Kettering Cancer Center, New York.

Miguel-Angel Perales, MD

Miguel-Angel Perales, MD

Various types of cellular therapy that can be used before or after hematopoietic stem cell transplant are being explored. The cellular therapy that has generated the most excitement recently is CAR T-cell therapy, and research suggests it may be possible to avoid transplant in selected patients who have a long-term response to this treatment.

Two CAR T-cell products targeting CD19 on the surface of B cells have been approved by the U.S. Food and Drug Administration (FDA): tisagenlecleucel, approved for the treatment of pediatric acute lymphoblastic leukemia [ALL] in patients up to age 25 and adults with large cell lymphoma, and axicabtagene ciloleucel, which is also approved for adults with lymphoma.

“Over the next year, we expect to have another CAR T-cell therapy approved for lymphoma [ie, lisocabtagene maraleucel]. All three of these CAR T-cell products are targeting CD19,” Dr. Perales explained. “Another CAR T-cell therapy, BB2121, is a B-cell maturation antigen–directed product designed to treat multiple myeloma, and that is expected to be approved in the near future as well.”

A slightly different anti-CD19 CAR T-cell therapy, KTE-X19, showed encouraging early results in a phase II study in patients with mantle cell lymphoma, 60 of whom received KTE-X19. Preliminary results in 28 patients with follow-up of over a year showed an overall response rate of 86% (95% confidence interval [CI] = 67%–96%), with a complete response rate of 57% (95% CI = 37%–76%). The 12-month rate of duration of response, progression-free survival, and overall survival were, respectively, 83% (95% CI = 60%–93%), 71% (95% CI = 50%–84%), and 86% (95% CI = 66%–94%). Medians were not reached.6

“This CAR is different from [axicabtagene ciloleucel] in that it includes a step to select the T cells to eliminate any potential leukemic cell from the product, avoiding the risk of transfusing the leukemic cell to the [CAR T cells],” Dr. Perales explained. “This product is probably a year away from FDA approval.”

Is There a Best CAR T-Cell Product?

“For most of these diseases, the best CAR T-cell product is the one we [in the transplant community] have in clinics,” Dr. Perales stated. “We have two products that are FDA-approved in large cell lymphoma, and soon we will have three. The companies will have their biases, the investigators will also have biases, and there will never be randomized studies to compare these products for efficacy, response rates, safety, feasibility, and turnaround time. It is unlikely that companies would sponsor those studies.”

CARs differ in two aspects—the first is the antigen they recognize on the tumor. The currently available CARs are directed to CD19. The second is the co-stimulatory domain. “If T cells don’t get a second signal, they don’t work as well,” Dr. Perales noted, explaining the need for a co-stimulatory domain.

Axicabtagene ciloleucel uses CD28 as the co-stimulatory component, whereas tisagenlecleucel and lisocabtagene maraleucel use 41BB. This leads to differences in the rate of expansion and the killing rate. Mouse models have shown that CD28 expands faster and kills more cancer cells than 41BB, although 41BB tends to promote for memory T cells, leading to a longer-lasting response.

“We know from clinical experience that axicabtagene ciloleucel is associated with more side effects, including cytokine-release syndrome and neurologic toxicity, now called immune effector cell–associated neurotoxicity syndrome. At day 28, response rates are higher for [axicabtagene ciloleucel] than for [tisagenlecleucel]. Using response rates at day 28 may be misleading. Patients care more about the longer term responses, and at 3 and 6 months, the response rates and survival rates for the two different types of CAR T-cell therapy seem to be similar,” Dr. Perales continued. “Long-term survival ranges from 40% to 50% with the FDA-approved CAR T-cell products.”

Registry Data on CAR T-Cell Therapy

Although there will never be a trial directly comparing the two types of CAR T-cell products, data are being reported to a national registry of patients treated with these therapies called the Cellular Immunotherapy Data Registry (CIDR) under the aegis of the Center for International Blood and Marrow Transplant Research (CIBMTR). Kite Pharma is required by the FDA to collect data on safety and response for the first 1,500 patients treated with its product (axicabtagene ciloleucel). Novartis, which has two indications for its product (tisagenlecleucel), has to submit data on the first 1,000 patients with ALL and the first 1,500 patients with lymphoma who receive this therapy.

“Once the CIDR collects these data, we can go back and do some data mining to compare the products ‘apples to apples’ and adjust treatment decisions using our findings. Some patient types may do better on one product or another, and it appears that older patients are receiving tisagenlecleucel more often,” Dr. Perales said. “Over the next 2 years, we will start to see studies that use the data from the CIDR to characterize any differences between the CAR T-cell products.”

A recent study at Memorial Sloan Kettering Cancer Center explored the safety profiles of the two types of CAR T-cell products and found no major differences, except for more frequent cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome with axicabtagene ciloleucel.7

“We are starting to see some papers in the literature making those comparisons, but we need larger studies to show the risk vs benefit of each type of CAR T-cell therapy for our patients,” Dr. Perales stated.

‘Off-the-Shelf’ CAR T-Cell Therapy

researchers are making inroads in developing an “off-the-shelf” CAR T-cell product that would have several advantages, including skirting the tedious, laborious process of manufacturing CAR T cells from each patient’s T cells, as well as using healthy T cells from volunteers to avoid using “exhausted” T cells from heavily treated patients with advanced disease.

Regarding “off-the-shelf” CAR T cells, Dr. Abutalib said: “The logistics involved in various manufacturing issues and treating with autologous CAR T cells adds a layer of complexity, which can be more efficiently managed with therapeutically successful ‘off‑the-shelf’ CAR T cells.”

“The use of ‘off-the-shelf’ CAR T cells is still very much investigational. This type of readily available product is made of T cells from a healthy donor and can be made ahead of time in batches that could treat up to 10 patients. I could get this type of product ‘freezer ready’ in a much more timely manner. This avoids contamination with a different patient’s cells in the custody chain,” Dr. Perales commented.

“Preliminary studies on ‘off-the-shelf’ CAR T cells for ALL have been presented at several meetings, including the 2019 ASH Annual Meeting,” Dr. Perales noted. “We have seen responses in adult and pediatric ALL with UCART19, but a number of these patients went on to receive a transplant.”

He continued: “At this stage, ‘off-the-shelf’ CAR T-cell therapy does not replace transplant. We need to see more mature results to determine if those patients will need transplant. There are at least half a dozen players in this space. When we have more data over the next 12 to 24 months, we will have a better sense of the role of ‘off-the-shelf’ CAR T cells.”

Impact of CAR T-Cell Therapy on Autologous Transplants

“It is a big challenge to determine the role of CAR T-cell therapy vis-à-vis transplant,” Dr. Perales continued. Autologous transplant is used primarily for myeloma and lymphoma. Allogeneic transplant utilizes donor stem cells primarily for acute leukemia, myelodysplastic syndrome, and to a much lesser extent, lymphoma and myeloma.

“We know the number of autologous transplants is going down in lymphoma, but the drop in transplant procedures has more to do with new drugs other than CAR T-cell therapy at this stage. CAR T cells are used in patients with lymphoma for whom transplant fails or who are not candidates for transplantation.”

Three large multicenter, multinational trials are comparing autologous transplant with CAR T-cell therapy in patients with lymphoma who relapse after first-line chemotherapy. Dr. Perales said that a study by Kite Pharma has been completed, and results should be available in about 18 months. He noted that Novartis and Celgene/Bristol-Myers Squibb have open studies asking the same question.

“If those studies are positive, CAR T-cell therapy could replace autologous transplant in this setting. On the other hand, if results are similar, cost will become a big issue. CAR T-cell therapy is more expensive than autologous transplant at this stage,” Dr. Perales noted.

Currently, there are no randomized studies to compare CAR T-cell therapy to autologous transplant in multiple myeloma. “Myeloma is a rapidly evolving space, and the role of transplant is being questioned. However, it remains the most common indication for autologous hematopoietic stem cell transplant,” Dr. Perales said.

Allogeneic Transplant

In lymphoma, if a patient relapses after an autologous transplant, the current standard of care is to try and achieve remission and perform an allogeneic (donor) transplant, which can achieve cure in about 40% of patients.

“I would argue that in 2020, CAR T-cell therapy should be the standard of care for [patients with lymphoma] who relapse after an autologous transplant.”
— Miguel-Angel Perales, MD

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“I would argue that in 2020, CAR T-cell therapy should be the standard of care for [patients with lymphoma] who relapse after an autologous transplant. If a patient can achieve remission on CAR T-cell therapy, I would monitor the patient and discuss allogeneic transplant down the road if necessary,” Dr. Perales stated. “I predict that CAR T-cell therapy will push aside allogenic transplant for patients with lymphoma.”

Addressing cost, he noted, “The approved CAR T-cell products cost $373,000 for patients with lymphoma and $475,000 for those with leukemia in the United States. That’s just the cost to manufacture the cells. If you use CAR T-cell therapy as a bridge to transplant, you double the cost of care, and that is not economically sustainable.”

“I concur,” Dr. Abutalib commented. “However, there remain major economic and logistic barriers to getting patients safely to just CAR T-cell therapy.”

Pediatric Advances in Haploidentical Transplant

Rupert Handgretinger, MD, Professor of Pediatrics and Chairman of the Department of General Pediatrics and Hematology/Oncology at the Children’s University Hospital in Tuebingen, Germany, discussed advances in pediatric transplantation presented at HAPLO2019.

Rupert Handgretinger, MD

Rupert Handgretinger, MD

New therapeutic approaches to haploidentical transplantation in children include the use of CD45RA-depleted donor lymphocyte infusion, which accelerates the immune recovery posttransplant and thus reduces the risk of viral reactivations and severe viral diseases. Repeated doses of CD45RA-depleted donor lymphocytes were safe and did not cause graft-vs-host disease.

“It seems that CD45RA-depleted donor lymphocyte infusion will play an important future role in the setting of haploidentical transplantation using T-cell receptor (TcR) alpha/beta–depleted stem cells. It has also been shown that TcR alpha/beta depletion in pediatric haploidentical transplantation gives the same outcome as matched unrelated donor transplants. In addition, research shows that posttransplant cyclophosphamide with T-cell–replete bone marrow is an option in pediatric haploidentical transplantation,” Dr. Handgretinger stated.

At the symposium, new data were presented using a combination of TcR alpha/beta depletion and posttransplant cyclophosphamide in patients who would not have endured an intensive conditioning regimen.

“The rationale for the combination is that the reduced conditioning regimen is not effective enough to eliminate patients’ residual T cells, which would then lead to rejection of a T-cell–depleted graft. After infusion of the TcR alpha/beta–depleted mobilized peripheral stem cells, the residual recipient T cells will become alloreactive and will then be eliminated by cyclophosphamide administered on days +3 and +4. This approach was successfully used in patients with severe immunodeficiencies,” Dr. Handgretinger explained.

“This combination could offer a curative transplant for patients who would otherwise not be eligible for a conventional transplant. It might be the basis for a merely immunologic conditioning of patients with nonmalignant diseases,” he continued.

Currently, haploidentical transplantation with either T-cell–depleted or T-cell–replete stem cells is a viable option for children who are in need of a transplant. There is no longer any difference in the outcome with this strategy compared to matched unrelated donor transplants. The haploidentical approach avoids lengthy donor searches, during which patients might have progression of their underlying disease.

“It seems that CD45RA-depleted donor lymphocyte infusion will play an important future role in the setting of haploidentical transplantation using T-cell receptor alpha/beta–depleted stem cells.”
— Rupert Handgretinger, MD

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“Unfortunately, it is not documented how many patients succumb to their disease during a matched unrelated donor search. It could well be that in an intent-to-treat analysis, the haploidentical approach might give better outcomes,” Dr. Handgretinger suggested.

According to Dr. Handgretinger, the long-term effects of haploidentical transplantation are mainly caused by the intensity of the conditioning regimens. Therefore, efforts are made to reduce intensive regimens without risking the increase of relapses in malignant diseases. Since the haploidentical donor can be available any time after transplant, posttransplant strategies may be envisioned to reduce the risk of relapse.

Such strategies include the use of CD45RA-depleted donor T cells, donor-derived natural killer (NK) cells, donor-derived NK-CAR cells, or CAR T cells. In the case of viral diseases, haploidentical virus-specific T cells can be manufactured rapidly and given safely to patients. Reducing the conditioning regimen would also result in less morbidity and mortality. This is of special interest in patients with nonmalignant diseases, and the goal for these patients is to ensure engraftment of haploidentical stem cells with minimally cytotoxic and more immunologic conditioning regimens.

“Since HAPLO2018, the outcome of haploidentical transplantation is improving. More centers have implemented this approach. It is questionable whether [matched unrelated donor] transplants in children are superior and whether haploidentical transplantation should be the first choice in the absence of a matched sibling donor,” Dr. Handgretinger stated. 

DISCLOSURE: Dr. Ciurea holds stock or other ownership interests in CytoSen; has served in a consulting or advisory role for CytoSen, Kiadis Pharma, and MolMed; has received research funding from Miltenyi Biotec; and has been reimbursed for travel, accommodations, or other expenses by CytoSen, Kiadis Pharma, and MolMed. Dr. Abutalib has served on advisory boards for AstraZeneca and Partner Therapeutics. Dr. Perales holds stocks or other ownership interests in NexImmune; has served in a consulting or advisory role for AbbVie, Incyte, Kite Nektar, NexImmune, Novartis, Medigene, Merck, MolMed, Seattle Genetics, Servier/Pfizer, and Takeda; and has received institutional research funding from Incyte, Kite, and Miltenyi Biotec. Dr. Handgretinger is co–patent holder of the TcR alpha/beta depletion system and has received research support from Miltenyi Biotech.


1. Srour SA, Saliba RH, Bittencourt MCB, et al: Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation. Am J Hematol 94:1382-1387, 2019.

2. Walter RB, Buckley SA, Pagel JM, et al: Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplant for AML in first and second complete remission. Blood 122:1813-1821, 2013.

3. Ciurea SO, Bittencourt MCB, Milton DR, et al: Is a matched unrelated donor search needed for all allogeneic transplant candidates? Blood Adv 2:2254-2261, 2018.

4. Fitzhugh C: Haploidentical transplantation for sickle cell disease. 2019 Haploidentical Transplantation Symposium. Presented December 5, 2019.

5. Bolaños-Meade J, Cooke KR, Gamper CJ, et al: Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: A prospective clinical trial. Lancet Haematol 6:e183-e193, 2019.

6. Wierda WG, Bishop MR, Oluwole O, et al: Updated phase I results of Zuma-3: KTE-X19, an anti-CD19 chimeric antigen receptor T cell therapy, in adult patients with relapsed/refractory acute lymphoblastic leukemia. Biol Blood Marrow Transplant 25(3 suppl):S185, 2018.

7. Pennisi M, Jain T, Santomasso BD, et al: Comparing CAR T-cell toxicity grading systems: Application of the ASTCT grading system and implications for management. Blood Adv 4:676-686, 2020.