HSCT · Childhood Myelodysplastic Neoplasms

MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered the optimal approach to treatment for pediatric patients with MDS. Although matched sibling donor transplant is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[1-5]

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Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplant before progression to late MDS or acute myeloid leukemia (AML) should be considered. HSCT should especially be considered when transfusions or other treatments are required, as is usually the case in patients with severe symptomatic cytopenias.[4,6] The 8-year disease-free survival (DFS) rates for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[6][Level of evidence C2] A 3-year DFS rate of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS when the transplants were done after the year 2001.[7][Level of evidence C2]

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When making treatment decisions, certain data should be considered, including the question of whether chemotherapy should be used in high-risk MDS. For example, survival rates as high as 80% have been reported for patients with early-stage MDS who proceeded to transplant within a few months of diagnosis. Additionally, early transplant and no pretransplant chemotherapy have been associated with improved survival in children with MDS.[8][Level of evidence C1]; [9] A retrospective analysis suggested that azacitidine and venetoclax may have a role in the cytoreduction of disease before HSCT in children with MDS. To date, reports of patients with advanced MDS who received venetoclax-based therapy are anecdotal.[10] While results differ in published series, this regimen might prove to be an effective bridge to HSCT. Azacitidine and venetoclax are being prospectively studied as treatment options for children with MDS.

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DFS rates have been estimated to be 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[4,6,11-13] While nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders. However, these regimens may be reasonable in the setting of a clinical trial or when a patient’s organ function is compromised in such a way that a myeloablative regimen would be intolerable.[14-17]; [18][Level of evidence C1]

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Evidence (HSCT):

The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[11] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (RAEB) (n = 33), refractory anemia with excess blasts in transformation (RAEB-T) (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor or randomly assigned to either autologous HSCT or chemotherapy.

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The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[11] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (RAEB) (n = 33), refractory anemia with excess blasts in transformation (RAEB-T) (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor or randomly assigned to either autologous HSCT or chemotherapy.

Patients with refractory anemia or RAEB had a lower remission rate (45%). Patients with RAEB-T (69%) or AML with a history of MDS (81%) had similar remission rates compared with those with de novo AML (77%).

The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[11] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (RAEB) (n = 33), refractory anemia with excess blasts in transformation (RAEB-T) (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor or randomly assigned to either autologous HSCT or chemotherapy.

The 6-year survival rates were lower for those with refractory anemia or RAEB (28%) and RAEB-T (30%).

The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[11] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (RAEB) (n = 33), refractory anemia with excess blasts in transformation (RAEB-T) (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor or randomly assigned to either autologous HSCT or chemotherapy.

Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (survival rates, 50% vs. 45%, respectively).

The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[11] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (RAEB) (n = 33), refractory anemia with excess blasts in transformation (RAEB-T) (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor or randomly assigned to either autologous HSCT or chemotherapy.

Allogeneic HSCT appeared to improve survival (P = .08).

Based on the results of the EWOG-MDS 98 study, HSCT was verified as an important therapeutic approach necessary to achieve prolonged survival. For many patients, HSCT is the sole therapy received.[19] Children with RAEB (n = 53), RAEB-T (n = 29), and myelodysplasia-related AML (n = 15) were treated with an HSCT from various sources (related and unrelated) using the preparative regimen of busulfan, cyclophosphamide, and melphalan. Among this group, 73 were treated without the use of intensive therapy before the HSCT preparative regimen.

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Based on the results of the EWOG-MDS 98 study, HSCT was verified as an important therapeutic approach necessary to achieve prolonged survival. For many patients, HSCT is the sole therapy received.[19] Children with RAEB (n = 53), RAEB-T (n = 29), and myelodysplasia-related AML (n = 15) were treated with an HSCT from various sources (related and unrelated) using the preparative regimen of busulfan, cyclophosphamide, and melphalan. Among this group, 73 were treated without the use of intensive therapy before the HSCT preparative regimen.

Children with a diagnosis of RAEB and RAEB-T had equivalent event-free survival (EFS) rates of 63% (95% confidence interval [CI], 49%–77%) and 64% (95% CI, 46%–82%), respectively.

Based on the results of the EWOG-MDS 98 study, HSCT was verified as an important therapeutic approach necessary to achieve prolonged survival. For many patients, HSCT is the sole therapy received.[19] Children with RAEB (n = 53), RAEB-T (n = 29), and myelodysplasia-related AML (n = 15) were treated with an HSCT from various sources (related and unrelated) using the preparative regimen of busulfan, cyclophosphamide, and melphalan. Among this group, 73 were treated without the use of intensive therapy before the HSCT preparative regimen.

For those with a morphological marrow blast percentage before HSCT of less than 5%, 5% to 20%, or 20% or higher, the EFS rates were 62% (95% CI, 41%–83%), 65% (95% CI, 50%–80%) and 45% (95% CI, 23%–67%), respectively.

Based on the results of the EWOG-MDS 98 study, HSCT was verified as an important therapeutic approach necessary to achieve prolonged survival. For many patients, HSCT is the sole therapy received.[19] Children with RAEB (n = 53), RAEB-T (n = 29), and myelodysplasia-related AML (n = 15) were treated with an HSCT from various sources (related and unrelated) using the preparative regimen of busulfan, cyclophosphamide, and melphalan. Among this group, 73 were treated without the use of intensive therapy before the HSCT preparative regimen.

In the entire cohort (n = 97), patients who received low-dose therapy or no therapy before the preparative regimen (n = 73) had similar EFS rates compared with those who received prior intensive chemotherapy (58% [95% CI, 46%–70%] vs. 62% [95% CI, 42%–82%]).

Based on the results of the EWOG-MDS 98 study, HSCT was verified as an important therapeutic approach necessary to achieve prolonged survival. For many patients, HSCT is the sole therapy received.[19] Children with RAEB (n = 53), RAEB-T (n = 29), and myelodysplasia-related AML (n = 15) were treated with an HSCT from various sources (related and unrelated) using the preparative regimen of busulfan, cyclophosphamide, and melphalan. Among this group, 73 were treated without the use of intensive therapy before the HSCT preparative regimen.

The outcomes of patients who received unrelated donor cells were like the outcomes of patients who received matched-family donor cells.

A single-institution retrospective analysis reported on 37 consecutive children with various types of MDS who underwent HSCT using various donor types. Some patients were treated with pre-HSCT chemotherapy (n = 7).[8]

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A single-institution retrospective analysis reported on 37 consecutive children with various types of MDS who underwent HSCT using various donor types. Some patients were treated with pre-HSCT chemotherapy (n = 7).[8]

In multivariate analysis, improved DFS was associated with avoiding pre-HSCT chemotherapy (relative risk [RR], 0.30; P = .03) and a shorter interval (<140 days) between diagnosis and HSCT (RR, 0.27; P = .02).

A single-institution retrospective analysis reported on 37 consecutive children with various types of MDS who underwent HSCT using various donor types. Some patients were treated with pre-HSCT chemotherapy (n = 7).[8]

In the 16 children who did not receive pre-HSCT chemotherapy and underwent transplant fewer than 140 days from diagnosis, the 3-year overall survival (OS) and DFS rates were both 80% (95% CI, 51%–93%).

When analyzing these results, it is important to consider that the subtype RAEB-T is likely to represent patients with overt AML, while refractory anemia and RAEB represents MDS. The World Health Organization classification has omitted the category of RAEB-T, concluding that it is essentially AML.

Because MDS in children is often associated with inherited predisposition syndromes, reports of transplant in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year OS rate has been reported to be 33% to 55%.[20,21][Level of evidence C1]

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While some patients with inherited predisposition syndromes require significant modification of their transplant approaches because of excess toxicity (e.g., Fanconi anemia), other syndromes have no detectable excessive toxicity associated with the transplant process. Inherited GATA2 deficiency is a good example of the latter. One study compared HSCT outcomes of 65 children with GATA2 germline pathogenic variants and MDS with the outcomes of 404 children with MDS and wild-type germline GATA2. Rates of DFS, relapse, and nonrelapse mortality were similar in the two populations.[22]

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Second transplants have also been used in pediatric patients with MDS/myeloproliferative disorders who experience relapse or graft failure. The 3-year OS rates were 33% for those who underwent a second transplant after relapse and 57% for those who underwent a second transplant after initial graft failure.[23][Level of evidence C1]

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For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered the standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but there are concerns that such treatment could accelerate conversion to AML.[24]

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