Clinical Case of the Month – Acute myeloid leukaemia secondary to acquired aplastic anaemia

March 2024 Clinical Case of the Month

Title: Acute myeloid leukaemia secondary to acquired aplastic anaemia.

Physician's expert perspective: Pedro Henrique de Lima Prata, Hematology Department, Saint-Louis Hospital, Paris, France

A 57-year-old woman was diagnosed with non-severe aplastic anemia with a positive paroxysmal nocturnal hemoglobinuria clone (0.2% on neutrophils and monocytes) in 2019; no treatment was required at that moment. Her personal history was marked by a healed hepatitis C and systemic lupus erythematosus, for which she was stable under low-dose steroids and hydroxychloroquine.

In 2023, she sought medical attention because she felt tired; her performance status was 1. Her CBC showed Hb 73g/L, reticulocyte count at 11 x10⁹/L, leukocytes at 2.4 x10⁹/L (0.2 x10⁹/L neutrophils) and 13 x10⁹/L platelets. A marrow smear, flow cytometry, and cytogenetics confirmed the diagnosis of M0 acute myeloid leukemia with normal karyotype with a marrow blast count of 33%. There were no mutations among FLT3, IDH1/2, or NPM1 genes. There were no other significant comorbidities, and her workup was unremarkable.

She had one haplo-identical brother, one HLA-different sister, and three haplo-identical children. There were no available 10/10 or 9/10 on the registry. She had no donor-specific antibodies against her potential haplo-identical donors.

Which of the following is an appropriate therapy?

A. Induction chemotherapy. If remission is achieved, three cycles of aracytine consolidation since no HLA-match donor is available.
B. Hypomethylating agents in combination with a BCL-2 inhibitor (venetoclax) until disease progression.
C. Induction chemotherapy followed by consolidation with haplo-identical transplantation using a reduced-intensity conditioning regimen.
D. Induction chemotherapy followed by consolidation with haplo-identical transplantation using a myeloablative conditioning regimen.

Expert perspective by Pedro H Prata:

Clonal evolution into myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) is a troubling late event among immune aplastic anemia patients, occurring among around 10% of non-transplanted patients by 10 years after diagnosis.^1,2 The prognosis of progressed patients is poor because of high-risk morphological (excess of blasts), karyotypic (monosomy 7), and molecular characteristics.^1,3

Lack of complete response, older age at marrow failure onset, and (perhaps) non-severe aplastic anemia not requiring treatment present a higher risk of malignant clonal evolution.^1,4 Stress hematopoiesis and marrow’s microenvironment chronic inflammation might profit myeloid-disease-associated mutated clones.^5–9

The only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). The use of standard chemotherapy or hypomethylating agents is associated with high rates of hematologic toxicity in patients with post-AA MDS/AML.¹⁰ The “healthy” hematopoietic stem cell pool was already poor before the transformation. At remission, the likelihood these polyclonal cells will be sufficient to sustain hematopoiesis is dim.

The first study to address survival following HSCT for MDS/AML found a 5-year overall survival of 45% ± 9%, better for patients untreated or in MDS/AML remission than patients with refractory disease.³More recently, the EBMT Severe Aplastic Anemia working party re-studied survival following HSCT for secondary MDS/AML following AA/PNH.¹¹ With a cohort of 278 patients and a median age at AA/PNH diagnosis of 34.7 (20.5-51.7) years and a median follow-up of 5 (4.3 - 5.9) years, the 5-year overall survival was 65% for the entire cohort. A subgroup analysis did not find a significant 5-year OS difference among MDS or AML patients: 62, and 60%, respectively (p=0.3). The leading causes of death were transplant-related toxicities (75% for MDS) and relapse or progression for AML (43.8%). When stratifying by conditioning regimen intensity, the 5-year NRM was 34% (19-40) for myeloablative (MAC) vs. 18% (9-26) for reduced-intensity (RIC, p=0.025), with similar incidence of relapse in both groups (4 vs 10% for MAC and RIC, respectively, p=0.2).

Clinicians should indicate HSCT with discretion for post-AA/PNH MDS, considering the transplant toxicity, especially with MAC, and the risk of primary disease progression. For patients with AML and a high risk of relapse, early tapering of immunosuppressive agents and post-transplant maintenance, such as hypomethylating agents and donor lymphocyte infusion, should be considered.

Case follow-up:

This patient received induction chemotherapy based on daunorubicin/cytarabine liposome (Vyxeos) followed by haplo-identical HSCT consolidation using a RIC conditioning regimen. She is currently feeling well, at home, in complete remission, and without GvHD three months after transplant.

Correct Answer: C

References:

1. Gurnari, C. et al. Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria. J Clin Oncol 41, 132–142 (2023).
2. Scheinberg, P. & Young, N. S. How I treat acquired aplastic anemia. Blood 120, 1185–1196 (2014).
3. Hussein, A. A. et al. Outcome of allogeneic stem cell transplantation for patients transformed to myelodysplastic syndrome or leukemia from severe aplastic anemia: A report from the mds subcommittee of the chronic malignancies working party and the severe aplastic anemia worki. Biology of Blood and Marrow Transplantation 20, 1448–1450 (2014).
4. Socie, G. et al. Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party. N Engl J Med 329, 1152–1157 (1993).
5. Muto, T. et al. TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity. Cell Stem Cell 29, 298-314.e9 (2022).
6. Vyas, P. Genetic and non-genetic mechanisms of inflammation may promote transformation in leukemia. Cell Stem Cell 29, 184–186 (2022).
7. Muto, T. et al. Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs. Nat Immunol 21, 535–545 (2020).
8. Hormaechea-Agulla, D. et al. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 1–15 (2021) doi:10.1016/j.stem.2021.03.002.
9. Rajan, V. et al. Stress hematopoiesis induces a proliferative advantage in TET2 deficiency. Leukemia 36, 809–820 (2022).
10. Connor, M. P. et al. Hypomethylating Agents Are Associated with High Rates of Hematologic Toxicity in Patients with Secondary MDS/AML That Develops after Acquired Aplastic Anemia. Blood 142, 2720–2720 (2023).
11. Prata, P. H. et al. Transplant Outcomes for Acute Myeloid Leukemia or Myelodysplastic Syndromes Secondary to Acquired Aplastic Anemia or Paroxysmal Nocturnal Hemoglobinuria: A Report from the EBMT Severe Aplastic Anemia Working Party. Blood 142, 704–704 (2023).
     

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