General AML

Monthly editorial theme | An introduction to the use of transplantation for the treatment of AML

This month’s editorial article looks at the use of hematopoietic stem cell transplantation (HSCT) as a treatment option for acute myeloid leukemia (AML). This article will look at the different stem cell sources used for HSCT, the patients selected for an HSCT, and the current major issues in the pre- and post-transplant setting.

Transplant strategies for AML

Today, the only curative approach to treat patients with AML is the administration of high-dose chemotherapy followed by allogeneic HSCT (allo-SCT). Although autologous HSCT (auto-SCT) may still be an option for certain patients with favorable or intermediate risk AML, its use has been debated due to the fact that AML is a blood and bone marrow malignancy, thus transplantation with the patient’s own cells runs the risk of giving back some of the patient’s leukemia cells.1 In contrast, during the process of allo-SCT, cells from a donor are infused. This provides an additional benefit, called the graft-versus-leukemia or tumor (GvL or GvT) effect, whereby the donor immune cells have the potential of recognising and eradicating remaining leukemia cells in the host, thus reducing the risk of relapse.2

Various donors can be used for an allo-SCT, while the best stem cell source remains to be from a human leukocyte antigen (HLA)-matched sibling donor (MSD). However, in approximately 70% of the cases such donors are unavailable, leaving the next best option of an HLA-matched unrelated donor (MUD).3 For patients where MSD or MUD are unavailable, a partially HLA-matched related donor can be used. This is referred to as haploidentical transplant (HD) and is usually a 50% HLA-match. In the past, HD has been associated with a slow immune reconstitution and high mortality from infections. Today, the use of post-transplant management treatments, like post-transplant cyclophosphamide (PTCy), reduces mortality and has made HD a viable option for patients with AML. This was further discussed by Arnon Nagler in his interview4 with the AML Global Portal (AGP) during the 2019 European Society for Blood and Marrow Transplantation (EBMT) meeting (video below). Nevertheless, HD still leads to inferior outcomes when compared to MSD in patients with AML (read AGP article here). Other donor types include cells from umbilical cord (read AGP article here) or from HLA-mismatched unrelated donors (MMUD).2 The impact of donor type on the outcomes of allo-SCT has recently been explored in an article by the AGP here. The authors of the study concluded that the traditional hierarchy of donors (MSD, MUD, and then others) remains true in patients with AML and should be used as a treatment algorithm.

VIDEO INTERVIEW:  EBMT 2019 | Haploidentical hematopoietic transplantation: current status and future perspectives

How to choose the right patients for transplantation

Choosing the right patient to receive transplantation following chemotherapy is crucial for maximising outcomes and reducing the risk of relapse and toxicity. As mentioned by Uwe Platzbecker in his AGP interview during the 2019 EBMT meeting (video below), there are two main considerations when choosing the right candidate for allo-SCT:

  1. Patient-related criteria, like age, frailty, comorbidity burden as scored by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)5, and general clinical status;
  2. Evaluation of the potential benefit from allo-SCT for every patient based on their European LeukemiaNet (ELN) risk stratification6

According to the ELN guidelines, patients are classified as favorable-risk, intermediate-risk, or poor-risk depending on the possibility of disease relapse. Patients with favorable-risk are usually not considered for allo-SCT after achieving their first complete remission (CR1), as the risk of toxicity and serious side effects outweighs the potential benefit from allo-SCT. For these patients, auto-SCT instead of chemotherapy after CR1 could be beneficial (read AGP article here). On the contrary, allo-SCT at CR1 is a common strategy for poor-risk patients with AML. In the case of intermediate-risk patients (the majority of patients with AML), the most suitable treatment option is less clear.6 Due to the high relapse rates seen in AML, allo-SCT has also been considered as a potential treatment strategy in second remission (CR2), although outcome is inferior compared to allo-SCT performed in CR1.7 In a recent study, summarized here by the AGP, it seems that myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) lead to similar outcomes after allo-SCT in CR2, however more prospective trials are needed to tailor them for maximum efficacy and minimum toxicity.7 To date, it is evident that clinical decisions to perform transplantation need to be made on an individual basis. Recently, measurable residual disease (MRD) as a marker for disease severity and relapse risk has emerged as an important factor that can guide treatment decisions in the context of HSCT and has been reviewed in depth here by the AGP.

VIDEO INTERVIEW:  EBMT 2019 | Considerations for transplantation in AML

Post-transplant issues & how to tackle them

Regardless of the advances in the transplantation field, allo-SCTs are associated with two main post-transplant issues: disease relapse and graft-versus-host disease (GvHD).

There is still a considerable number of patients that relapse after HSCT. At the moment, the best strategies to decrease the risk of post-transplantation relapse include:

  1. Pre- and post-transplantation MRD assessment to guide treatment (read more here);
  2. Targeted agents to further reduce tumor load and support the graft-versus-leukemia (GvL) effect

Such agents include the use of FMS-like tyrosine kinase-3 (FTL3) inhibitors that are shown to delay disease relapse and to potentiate the GvL effect in patients with FLT3 mutations after allo-SCT.7 Multiple pre-clinical and clinical trials are currently underway to examine the efficacy of other targeted inhibitors, like sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, and midostaurin, amongst others.8 Another drug that has been shown to prevent disease relapse and to potentially increase the GvL effect is azacitidine. This is a hypomethylating agent that is currently used as a safe and effective prophylactic therapy in high-risk patients following allo-SCT (read AGP article here).9

Charlie Craddock provided an extensive presentation on the strategies for GvL effect optimization at the 2019 EBMT meeting (see full article on the AGP here):

  1. Optimization of cytoreductive conditioning regimens
  2. Selection of the correct stem cell source
  3. Leukemia-specific antigen targeting as maintenance therapy
  4. Development of effective salvage regimens

VIDEO INTERVIEW: American Society of Clinical Oncology (ASCO) 2019 | Who should get azacitidine after transplant?

GvHD remains a major post-transplant challenge, occurring when transplanted donor cells start attacking host cells and tissues.10 There are two main strategies used today to prevent GvHD:

  1. The use of conditioning with T-cell depleting agents, like PTCy or anti-thymocyte globulin (ATG)
  2. The use of immunosuppressive drugs, like cyclophosphamide (CyP) or tacrolimus as a backbone, in combination with methotrexate (MTX) or mycophenolic acid (MPA)

In a clinical trial, PTCy has shown superior outcomes when compared to ATG in patients undergoing HD transplant, leading to improved overall survival, leukemia-free survival, and GvHD-relapse free survival. The results of this study were discussed by Arnon Nagler in his interview with the AGP at European Hematology Association (EHA) 2019. A comprehensive review on available treatments for GvHD prophylaxis and their efficacies has been published here by our GvHD Hub.

VIDEO INTERVIEW: EHA 2019 | Should we use PTCy or ATG as GvHD prophylaxis in haploidentical stem cell transplantation?

In patients who develop severe GvHD, systemic administration of steroids remains the first choice of treatment. Treating GvHD is considered by many as a double-edged sword, since on one side it is necessary, but on the other hand it may hinder the GvL effect, thus contributing to potential disease relapse. Further research is needed to clarify the role of GvHD treatment on the GvL effect and to establish the best agent to treat GvHD without hindering the benefits of graft transplantation to the host. Some patients do not respond to post allo-SCT corticosteroids and are classified as steroid-refractory GvHD patients. These patients have a high mortality rate after allo-SCT with a 1-year survival between 30-35%. Many novel approaches are being tested for these patients with the Janus kinase 1/2 (JAK1/2) inhibitor, ruxolitinib, and the Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, being recently approved by the Food and Drug Administration (FDA) for steroid-refractory GvHD.11,12

VIDEO INTERVIEW: EHA 2019 | What are the current treatment recommendations for acute GvHD and the promotion of the GvL effect?

Can the new treatments for AML reduce the need for transplantation?

With the recent therapeutic advances in the field of AML, one major question arises: Can these advances in diagnostics and new therapies replace allo-SCT? During the 1st National Cancer Research Institute (NCRI) AML academy meeting, AGP was pleased to film the headline debate on recently licensed drugs versus recent advances in transplantation, which can be accessed here. Although an unresolved issue, it is evident that some of the new treatments lack the toxicity associated with allo-SCT and have demonstrated improved survival rates. Moreover, with new diagnostic tools, the identification of the right subgroups of patients who may benefit from a transplant-free and more targeted approach will be feasible. One such novel approach to AML treatment is the use of CAR-T cells. Their use as monotherapy or in combination with allo-SCT for the treatment of relapsed or refractory AML is currently under consideration and of great interest in the field. More details on the potential of CAR-T cell therapy for AML can be found here in a recently published article by the AGP. However, it is too early to say whether these new treatment approaches can replace allo-SCT as a curative approach to treat AML. This topic was discussed by Gert Ossenkoppele in the interview with the AGP shown below.

VIDEO INTERVIEW: EHA 2019 | What is the clinical value of new drugs in AML?

Conclusions

Despite the curative potential conferred by allo-SCT in patients with AML, there is still a high risk of non-relapse mortality (mostly due to severe GvHD) in addition to the risk of relapse associated with transplantation. This warrants the need for the development of either novel management and prophylactic therapies that can improve post-transplantation outcomes or of transplantation-free approaches for the treatment of AML. With numerous clinical trials underway with novel targeted agents as monotherapy or in combination, the future of AML treatment starts to look more promising.

References
  1. Helbig G. et al. Long-term outcome of autologous hematopoietic stem cell transplantation (AHSCT) for acute myeloid leukemia (AML)- single center retrospective analysis. Pathol Oncol Res. 2018 Jul; 24(3):469–475. DOI: 10.1007/s12253-017-0266-7
  2. Dickinson A. M. et al. Graft-versus-leukemia effect following hematopoietic stem cell transplantation for leukemia. Front Immunol. 2017 Jun; 8:496. DOI: 10.3389/fimmu.2017.00496
  3. Shouval R. et al. Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. Lancet Haematol. 2019 Nov; 6(11):e573–e584. DOI: 10.1016/S2352-3026(19)30158-9
  4. AML Global Portal. Arnon Nagler | EBMT 2019 | Haploidentical hematopoietic transplantation: current status and future perspectives. https://amlglobalportal.com/medical-information/arnon-nagler-ebmt-2019-haploidentical-hematopoietic-transplantation-current-status-and-future-perspectives. [Accessed 2019 Mar 11]
  5. Raimondi R. The comorbidity index. 2016 Apr 5. 42nd Annual Meeting of the EBMT, Valencia, ES
  6. Döhner H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26; 129(4):424–447. DOI: 10.1182/blood-2016-08-733196
  7. Gilleece M. H. et al. Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT. Leukemia. 2019 Jul 30. DOI: 10.1038/s41375-019-0527-4
  8. Wu M. et al. FLT3 inhibitors in acute myeloid leukemia. J Hematol Oncol. 2018 Dec 04; 11:133. DOI: 10.1186/s13045-018-0675-4
  9. AML Global Portal. EBMT 2019 | Prevention of relapse following allogeneic stem cell transplantation using azacitidine in patients with high-risk AML https://amlglobalportal.com/medical-information/ebmt-2019-prevention-of-relapse-following-allogeneic-stem-cell-transplantation-using-azacitidine-in-patients-with-high-risk-aml. [Accessed 2019 Mar 11]
  10. Nassereddine S. et al. Acute graft versus host disease: A comprehensive review. Anticancer Res. 2017 Apr; 37(4):1547–1555. DOI: 10.21873/anticanres.11483
  11. Incyte. FDA Approves Jakafi® (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. https://investor.incyte.com/news-releases/news-release-details/fda-approves-jakafir-ruxolitinib-treatment-patients-acute-graft. [Accessed 2019 Mar 11]
  12. IMBRUVICA® (ibrutinib). Study design for previously treated cGVHD https://www.imbruvicahcp.com/cgvhd/efficacy-data/study-design. [Accessed 2019 Mar 11]
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