Case study 18.1
The patient is a 65-year-old Caucasian male, in good health, with a coincidental finding of neutropenia [absolute neutrophil count (ANC): 1.07 × 103/µL] and macrocytic anemia [hemoglobin (Hgb): 10.5 g/dL; mean corpuscular volume (MCV): 102 fL]. He reports no known prior exposure to toxins. His other laboratory parameters, including platelet (PLT) and absolute reticulocyte counts, iron studies, and serum erythropoietin (EPO), red cell folate, and copper levels, were all unremarkable. However, since his plasma vitamin B12 level was slightly below the lower normal limit, he was given vitamin B12 supplementation without improvement in his macrocytic anemia. Additionally, his test for HIV was negative. Bone marrow biopsy revealed a bone marrow with low cellularity for age (20%), with 9% blasts, abnormal nuclear lobulation of granulocytes, normal iron stores, and no increase in reticulin. His karyotype did not reveal any cytogenetic abnormalities. Finally, his flow cytometry analysis excluded large granular lymphocytic disease and paroxysmal nocturnal hemoglobinuria. The patient is sent to your hematopoietic stem cell transplantation (HSCT) clinic for evaluation for transplant.
• What is the best next step in management?
This patient is affected by myelodysplastic syndrome (MDS), which is consistent with refractory anemia with excess blasts-2 (RAEB-2) and an International Prognostic Scoring System (IPSS) score of 1.5 (intermediate-2). The IPSS is based on the percentage of blasts, number of cytopenias and cytogenetics, and median survival ranges from 5.7 years for low risk (IPSS: 0) to 0.4 years for high risk (IPSS: 2.5–3.5), while the 25% estimated progression to acute myeloid leukemia (AML) ranges from 9.4 to 0.2 years, respectively. Allogeneic HSCT is the only curative modality for MDS. However, for patients with low-risk and intermediate-1 MDS, delayed HSCT maximizes overall survival, whereas for patients with intermediate-2 and high-risk MDS, HSCT at diagnosis maximizes overall survival, with 35–50% long-term disease-free survival. For patients in the intermediate-1 or low-risk group, a transplant is to be considered in the case of development of poor risk factors, such as low performance status, advanced age, a drop in blood counts, an increased number of blasts, cytogenetic abnormalities, or failure to respond to hypomethylating agents. Our patient is an ideal candidate for HSCT: age range <75 years, IPSS: 1.5, Karnofsky performance status: 90%, and no comorbidities. Furthermore, he has no uncontrolled infections at present, and organ functions are appropriate. Importantly, high-resolution human leukocyte antigen (HLA) typing revealed that one sibling was fully matched with the patient.
• Is induction therapy indicated prior to transplant? And if so, what is the optimal induction regimen?
The American Society for Blood and Marrow Transplantation (ASBMT) has not provided recommendations regarding the optimal intensity of the induction regimen, such as high-intensity chemotherapy (AML-like) or milder, hypomethylating agents before HSCT. Published data seem to favor a transplant performed with minimal burden of disease, especially in reduced-intensity conditioning (RIC) regimens that most heavily rely on the graft-versus-leukemia (GVL) effect. One possible “bias” is that remission induction selects responsive patients. Some data show that induction therapy may not be associated with superior outcome; however, this may be related to the stage of disease and/or cytogenetic risk, which are “critical” in reporting and analyzing results in HSCT clinical trials involving a biologically heterogeneous disease such as MDS. Therefore, randomized clinical trials or more homogeneous series are needed to answer this question. In addition, the optimal debulking therapy is an area of debate. There are limited data to conclude whether therapy with hypomethylating agents is superior to cytotoxic induction chemotherapy, although one interesting publication by Gerds et al. (2012) showed that 5-azacytidine compared with induction chemotherapy prior to HSCT was associated with a better one-year overall survival rate (57 vs. 36%, P = 0.24), lower nonrelapse mortality, and a lower relapse rate, but only the hazard for relapse was significantly lower. However, after adjustment for cytogenetic risk, IPSS score, and donor, the rates of post-HCT relapse for the two cohorts were similar. It also seems that an allogeneic HSCT performed earlier in the course of disease leads to better outcomes. For this patient, we decided to adopt cytoreductive therapy with 5-azacytidine, and restaging performed after the first cycle showed complete remission of disease. Peripheral blood hematopoietic stem cells from the matched related donor were collected and cryopreserved.
• What is the most appropriate intensity of the transplant conditioning regimen?
The lower relapse rate of myeloablative conditioning (MAC) regimens is counterbalanced by a higher degree of regimen-related toxicity and transplant-related mortality (TRM) precluding this option for older patients, who are frequently affected by MDS–AML. Although large retrospective studies have reported comparable results between MAC and RIC regimens in MDS (and AML), randomized controlled trials are undergoing comparing MAC and RIC regimens (e.g., NCT01339910). Although this study is based on a few different regimens, its results will shed light on this controversy. Alatrash et al. (2011) have previously demonstrated that the development of a busulfan–fludarabine MAC regimen with low TRM allowed transplantation in patients through the eighth decade of life. This patient received a matched related donor HSCT after a MAC regimen. We used peripheral blood hematopoietic progenitor cells that are granulocyte colony-stimulating factor mobilized; these cells have been associated with survival benefit, as compared with bone marrow progenitor cells, in patients undergoing MRD–HSCT for myeloid malignancies. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-dose methotrexate.
17: Management of Therapy-Related Myeloid Neoplasms
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
