December 6, 2018

Meir Rinde

Although many new drugs have been introduced for treating patients with hematologic malignancies, stem cell transplantation remains a vital part of the therapeutic paradigm, particularly for multiple myeloma and non-Hodgkin lymphoma.

Henry Chi Hang Fung, MD, FACP, FRCPE

Nearly 50 years after the first successful bone-marrow transplant to treat leukemia, the number of hematopoietic stem cell transplants (SCTs) performed annually continues to increase. Growth will continue in the coming years, predict experts in the field.

Transplants have become increasingly easy to perform, as research advances have broadened the pool of cell donors and reduced or eliminated graft-versus-host disease (GVHD) in more patients. Less intensive minitransplants and improvements in supportive care have opened up SCT to older recipients, particularly patients aged between 60 and 69 years. Although chimeric antigen receptor (CAR) T-cell therapies and many new drugs for blood cancers have emerged in recent years, these therapies are often used in conjunction with traditional transplants rather than supplanting them.

Broadly defined, cell transplant for cancer is poised to become only more common, said Henry Chi Hang Fung, MD, FACP, FRCPE, director of the Fox Chase—Temple University Hospital Bone Marrow Transplant Program in Philadelphia, Pennsylvania.

Expanded Donor-Cell Options

Questions about the future of cell transplantation programs “have been asked over the past 30 or 40 years, and transplant is still here,” Fung said. “The field has evolved rapidly. For example, the cellular therapies—CAR T-cells or engineered T-cells—are rapidly expanding, and they’re always done by transplant programs. FDA will only let transplant people do them. Transplant will be rapidly expanding, depending on how you define it.”Traditional SCT falls into 2 categories: autologous and allogeneic. In the autologous variety, a patient’s blood-forming stem cells are collected, chemotherapy is administered, and the cells are reinfused into the patient. Autologous SCT is a standard treatment for multiple myeloma (MM), which accounts for the largest number of transplants overall. Autologous is also the predominant type used to treat non-Hodgkin lymphoma (NHL) and Hodgkin disease.¹

In allogeneic transplant, the patient receives cells from a matching donor after undergoing a conditioning therapy, typically total body irradiation with or without chemotherapy. Allogeneic is used most often for acute myeloid leukemia (AML), as well as for myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute lymphocytic leukemia (ALL), and NHL.

To avoid GVHD and transplant failure, successful allogenetic transplants once required cell donation from an identical sibling or from a relative or unrelated donor who was a close human leukocyte antigen (HLA) match. In the early 2000s, researchers at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, found they could make half-matched cell donations work by giving high doses of the chemotherapy drug cyclophosphamide (Cytoxan) after a transplant. The drug killed off donor cells that would have attacked the patient while leaving intact the regulatory T cells that helped rebuild the recipient’s immune system.

Cyclophosphamide therapy al lowed greatly expanded use of donations from 50% HLA-matched family members and was widely adopted, contributing to a surge in such transplants since 2012 (Figure 1).

Figure 1. Allogeneic SCT Recipients in the United States by Donor Type¹

Trends in Stem Cell Sources

“Probably the biggest change in the last 5 years has been the use of half-matched donors or haploidentical stem cell transplant,” said John F. DiPersio, MD, PhD, a professor at Washington University School of Medicine in St. Louis, Missouri. “They’ve emerged onto the scene robustly and the numbers of haplo transplants are increasing. Most studies show that the outcomes are fairly similar to unrelated donor transplants. Now it’s conceivable that you can find a donor for nearly everyone, which was not the case in the past. We’ve seen this emerge and the growth of unrelated donor transplants has slowed.”An earlier major innovation in the 1980s and 1990s was the development of methods to harvest stem cells from blood rather than bone marrow. Peripheral blood stem cell (PBSC) transplantation is now standard in autologous transplant and is used in more than 75% of allogeneic SCTs.² PBSCs are easier to collect and produce faster engraftment, although they are associated with higher rates of chronic GVHD, which is of particular concern for pediatric patients who will live for many decades after treatment.

Bone marrow cells are still often used in patients aged under 18 years, accounting for half of the unrelated-donor transplants in that group, according to data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Another option is umbilical cord blood (UCB) transplant, which has less stringent HLA-matching requirements and has been particularly important for nonwhite patients for whom a matched unrelated donor cannot be located quickly. Cord blood has drawbacks: Engraftment is slower, infection is more common, and the smaller cell yields can make it impractical for adult patients, although cell expansion techniques and double transplants can mitigate that obstacle.

A bigger issue is increased competition from easier and less expensive half-matched donor SCT, which has contributed to a decline in UCB transplants in the past several years.

“Doing cord blood transplants well is much harder than doing haploidentical transplants,” said Geoffrey R. Hill, MD, FRACP, FRCPA, a full member of the Clinical Research Division of Fred Hutchinson Cancer Research Center and director of hematopoietic stem cell transplantation of the Fred Hutch/Seattle Cancer Care Alliance in Seattle, Washington. “Cord blood transplant won’t go away, but it will probably be limited to a smaller number of centers with a lot of experience who have very good outcomes, of which Seattle is one. Certainly, there are some emerging data that patients who still have evidence of leukemia or disease before the transplant are likely to do better from a disease point of view with cord blood transplant than with other types of transplant.”

In patients with acute leukemia or MDS with pretransplantation minimal residual disease, the risk of death was found to be significantly higher after transplant from an HLA-mismatched unrelated donor than after cord blood transplant (HR, 2.92; 95% CI, 1.52- 5.63; P = .001).³ The risk was also higher after HLA-matched transplant but not significantly so (HR, 1.69; 95% CI, 0.94-3.02; P = .08). Relapse was less likely in the cord blood group than in either of the other groups.

Figure 2. Age Trends for Autologous SCT Recipients¹

Older Patients, Better Outcomes

A cord blood unit from an independent center costs about $35,000, contributing to the higher expense of UBC transplants.^4,5 Although allogeneic transplants have generally become less expensive since the mid-2000s, the cost remains high.⁶ Fung said that at Fox Chase, costs run from $350,000 to $800,000 per patient, which is consistent with national estimates.⁷ He said he expects the average outlay to decline as hospitals try to cut costs and perform more transplants on an outpatient basis. Autologous transplant is also expensive but much less so, costing $80,000 to $100,000 per patient, Fung said.A generation ago, the upper age limit for allogeneic transplants was 55 years, Fung said; now it’s 75. Although comorbidities such as heart disease and chronic obstructive pulmonary disease still limit SCT eligibility to 40% to 50% of older patients, improvements in the prevention and treatment of infections in immunocompromised people have made transplant much safer for them, he said.

“The most important thing is that supportive care is much better. We have much better antibiotics, much better antifungals, and much better antivirals,” Fung said.

An example is the management of cytomegalovirus (CMV) disease, which led to the deaths of 1 in 5 transplant patients in the 1970s and 1980s.⁸ The mortality rate from CMV is now less than 2% thanks to better diagnostic tools and widespread use of preemptive therapy with ganciclovir and other antivirals. Last year, the FDA approved letermovir (Prevymis), a safer antiviral that was the first new drug for CMV in 15 years.⁹

The FDA is reviewing a supplemental new drug application for the use of ruxolitinib (Jakafi), for treating patients with GVHD after undergoing SCT who have had an inadequate response to corticosteroids. The JAK1/JAK2 inhibitor is approved for high-risk myelofibrosis and polycythemia vera.

As better supportive care made SCT safer, cyclophosphamide opened up allogeneic transplant to older patients who would otherwise face major survival risks from GVHD. Researchers also developed minitransplant or nonmyeloablative transplantation, which uses low-dose radiation or chemotherapy to suppress the immune system rather than destroy it. This therapy, called reduced-intensity conditioning (RIC), is used in patients aged more than 60 years who cannot tolerate standard high-dose regimens.

RIC takes advantage of the graft-versusdisease effect, in which donor T cells eliminate remaining cancer cells in the patient, and involves careful use of immunosuppressive drugs to facilitate engraftment.

“We used to think that when we did a transplant, we had to give them the maximum tolerated dose of chemotherapy or radiation, which in fact is unnecessary. We were giving too much,” Fung said. “In the minitransplant, we just give minimum chemotherapy to prevent rejection and then use the graft-versus-leukemia effect for the treatment. It was originally only for older patients, but subsequently we expanded it to even younger patients.”

The number of allogeneic transplants (allo-SCTs) has climbed fastest for patients aged more than 60 years, who now represent 30% of allo-SCT recipients, while the 70-plus group accounts for 4.6%, according to CIBMTR data. The trend is also robust in autologous SCT (auto-SCT): More than half of recipients for lymphomas and multiple myeloma are aged more than 60years and 12% are 70 years and older (Figure 2).

The treatment advances that extended SCT to older patients also contributed to improvements in survival generally. However, survival rates vary widely depending on the disease type and stage and other factors.

In auto-SCT for MM, the most frequently performed transplant, 3-year overall survival increased from 68% in 2001 to 2004 to 77% in 2009 to 2012, and early data suggest further improvement since then. The introduction of new drugs for induction or posttransplant consolidation, including thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade), have been important drivers of longer survival.¹⁰

In patients with NHL, the most recent available data show 5-year auto-SCT survival rates of 60% for B-cell lymphoma and 47% for T-cell lymphoma. The survival rate after allogeneic transplant, which is often used for high-risk NHL or after auto-SCT failure, was 51% for B-cell and 54% for T-cell lymphoma.¹¹

In auto-SCT for relapsed or refractory Hodgkin disease, 3-year survival from 2005 to 2015 was 84% and 70% for patients with chemosensitive and chemoresistant disease respectively.

For patients with AML, outcomes after allogeneic transplant diverge considerably depending on disease stage and remain poor for advanced disease. The 3-year survival rates after HLA-matched sibling transplant were 59%, 52%, and 27% for patients with early, intermediate, and advanced disease, respectively. Three-year survival was somewhat lower after unrelated donor transplant, at 52%, 49%, and 25%. Outcomes were better among pediatric patients, with survival rates of 69%, 60%, and 29% for those receiving HLA-matched sibling transplants.

“Diseases in older patients, especially AML, seem to be much more resistant to treatment. They often occur in the background of myelodysplastic syndrome, and those diseases are hard to cure,” DiPersio said.

Allogeneic transplants for early MDS resulted in 3-year survival rates of 52% and 49% for recipients of sibling and unrelated donor transplants, respectively. The corresponding probabilities for advanced MDS were 45% and 41%. For myelofibrosis and other MPNs, the survival figures were 54% and 46%, respectively, after unrelated donor SCTs, and 61% and 52% among HLA-matched sibling donor recipients.

New Drugs Introduced

In ALL, allo-SCT is primarily used with high-risk older adults and pediatric patients who relapse after chemotherapy, fail to achieve remission, or have high-risk disease. Adults receiving HLA-matched sibling transplants had 3-year survival rates of 59%, 39%, and 28% for early, intermediate and advanced disease, respectively. In the smaller pediatric cohort, the equivalent rates were 73%, 58%, and 40%, respectively, for those stages of disease. Survival rates were slightly lower for unrelated donor transplants, with the exception of advanced pediatric disease, for which 3-year survival was higher at 43%.Although use of SCT continues to expand, physicians say that more patients are now starting their treatment with new drug therapies rather than auto-SCT. These include ibrutinib (Imbruvica) for NHL, and pomalidomide (Pomalyst), carfilzomib (Kyprolis), ixazomib (Ninlaro), daratumumab (Darzalex), and elotuzumab (Empliciti) for MM. “The availability of these safer and more effective agents has raised doubts about using [auto-SCT] as first-line therapy,” a review of MM treatment stated.¹⁰

“There are so many new drugs in those diseases that a lot of the patients are now getting diverted to different kinds of treatment,” DiPersio said.

That said, debates over the role of auto-SCT have not yet led to its displacement, and DiPersio noted that it has been enhanced by new maintenance therapies such as lenalidomide and blinatumomab (Blincyto). “In spite of every study that’s been done with new agents, autologous stem cell transplant still has a powerful impact on disease-free and overall survival of myeloma patients,” he said. “In non-Hodgkin lymphoma, in diffuse large cell lymphomas in the right patients, as well as in Hodgkin patients, autologous transplant still represents a very effective therapy long term.”

Fung said he does not see any new drug replacing transplant for MM for at least another 5 years.

A big question is what role CAR T-cell therapies will play. Updated findings announced in June from a phase I study of the anti-BCMA CAR T-cell therapy bb2121 showed a median progression-free survival of 11.8 months for patients with relapsed or refractory heavily pretreated MM.¹² A Chinese study administered the BCMA-targeting therapy LCAR-B38M to 35 patients with relapsed or refractory MM and, of the 19 who were followed for a median of 4 months, 14 achieved a stringent complete response.¹³ A number of other studies of CAR T-cell therapy for MM are under way.

However, Fung noted that the total cost of treating a patient with either of the 2 approved CAR T-cell therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), can exceed $1 million when all expenses of care are included. He argued that it will be challenging to complete a phase III trial of CAR T cells for MM. “I’m sure CAR T cells are better [than SCT],” he said. “But you have to show the difference in a timely manner for a disease that has so many different options for treatment and that has such easy autologous stem cell transplant. You need to enroll 500 to 1000 patients. This is a billiondollar study. Who will pay a billion dollars?”

Hill disagreed. CAR-T for MM is “probably one of the most active fields, and that reflects that myeloma is a much more common disease than the other diseases that we’re using CAR T-cells in. The potential market penetration is quite high if they’re effective. While it’s true that the clinical studies are expensive, the market is [large],” he said.

If a new cellular therapy for MM does reach the clinic, it still may not replace SCT. Although the currently available CAR T-cell therapies may be used after failed SCT, they are also given as posttransplant consolidation, and Hill said they sometimes serve as conditioning therapies, providing deep remissions that make patients with advanced disease eligible for transplant.

“Personally, I think that new immunotherapies and transplantation are probably going to be complementary and often combinational,” Hill said. “I don’t see a time in the near future where one replaces the other.” More trials are needed to establish the role of CAR T-cell therapies, he said.

References

1. D’Souza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT) / CIBMTR [Center for International Blood and Marrow Transplant Research.] Summary Slides. Milwaukee, WI, and Minneapolis, MN: CIBMTR;2017. cibmtr.org/ReferenceCenter/ SlidesReports/SummarySlides/pages/index.aspx. Updated June 16, 2018. Accessed October 30, 2018.

2. Körbling M, Freireich EJ. Twenty-five years of peripheral blood stem cell transplantation. Blood. 2011;117(24):6411-6416. doi: 10.1182/blood-2010-12-322214.

3. Milano F, Gooley T, Wood B, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375(10):944-953. doi: 10.1056/NEJMoa1602074.

4. Donor & transplant costs. Kids beating cancer website. kidsbeatingcancer. com/programs-services/resources/donor-transplant- costs. Accessed October 30, 2018.

5. Bourgeois W, Ricci A, Jin Z, et al. Health care utilization and cost among pediatric patients receiving unrelated donor allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2018;23(3 suppl):S120-S121. doi: 10.1038/s41409-018-0308-0.

6. Ricci A, Jin Z, Bourgeois W, et al. Health care utilization and cost of allogeneic hematopoietic cell transplantation (alloHCT) in children with malignant and non-malignant diseases. Biol Blood Marrow Transplant. 2018;24(3 Suppl):S427. doi: 10.1016/j. bbmt.2017.12.509.

7. Bone marrow transplant cost. Costhelper.com website. health. costhelper.com/bone-marrow-transplants.html. Accessed October 30, 2018.

8. de la Cámara R. CMV in hematopoietic stem cell transplantation. Mediterr J Hematol Infect Dis. 2016;8(1):e2016031. doi: 10.4084/MJHID.2016.031.

9. Gagelmann N, Ljungman P, Styczynski P, Kröger N. Comparative efficacy and safety of different antiviral agents for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2018;24(10):2101-2109. doi: 10.1016/j. bbmt.2018.05.017.

10. Mahajan S, Tandon N, Kumar S. The evolution of stem-cell transplantation in multiple myeloma. Ther Adv Hematol. 2018;9(5):123-133. doi: 10.1177/2040620718761776.

11. Reddy NM, Oluwole O, Greer JP, et al. Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma. Exp Hematol. 2014;42(1):39-45. doi: 10.1016/j.exphem.2013.09.012.

12. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(15 suppl;abstr 8007). meetinglibrary.asco.org/record/160693/abstract.

13. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/ relapsed multiple myeloma. J Clin Oncol. 2017;35(18 suppl;abstr LBA3001). doi: 10.1200/JCO.2017.35.15_suppl.LBA3001.