oligoblastic aml

Should patient with refractory anemia with excess blasts or those with oligoblastic AML

receive induction therapy prior to allogeneic transplantation?



My answer is“Yes”



My answer is “Yes”

What is the evidence-based data?No randomized trials and retrospective studies are subject to selection bias

Outline• Terminology: RAEB-t , Oligoblastic AML • Type of induction therapy prior to HSCT• Does the disease burden at the time of HSCT

matter?• Will pre-transplantation therapy lead to lower

relapse rate and superior longer survival?• Pre-HSCT therapy with induction chemotherapy• Pre-HSCT therapy with DNA hypomethylating

agents • Strategies in preperation for HSCT and

Recommendations from the experts

Terminology

• Smoldering acute leukemia: blast 3-20%• Pauciblastic myeloid leukemia• Oligoblastic myelogenous leukemia• Refractory anemia with excess blasts

- Myelodysplastic syndrome: high risk• Acute leukemia with blast 20-30%

IPSS-Revised: Prognostic Variables

Greenberg et al Blood 2012

Rational for Pre-HSCT therapy

• Tumor debulking to reduce the risk of post-HSCT relapse

• Slow leukemic transformation• Reduce transfusion needs during the time

of donor search

The only curative treatment modality for high risk MDS is allogeneic hematopoietic cell

transplantation(HSCT)

Type of treatment prior to transplantation

• AML induction-type chemotherapy • Hypomethylating agent(HMA) therapy

Does the disease burden matter?• Outcomes are improved with lower disease

burden at the time of HSCT.• Retrospective analyses from EBMT and

NMDP showed an improved outcome in patients with lower disease burden at the time of HSCT.

- De Witte T, Suciu S, Verhoef G, et al. Blood 2001;98: 2326-31- Castro-Malaspina H, Jabubowski AA, Papadopoulos EB, et al. Biol Blood Marrow Transplant 2008; 14: 458-68


matter?• Pre-HSCT therapy with induction chemotherapy• Pre-HSCT therapy with DNA hypomethylating

agents • Will pre-transplantation therapy lead to lower

relapse rate and superior longer survival?• Strategies in preperation for HSCT and


Pre-HSCT therapy with induction chemotherapy

• Selection bias for patients with chemosensitive disease, favorable prognosis. Higher treatment-related toxicity.

- They might have favorable outcomes if not exposed to cytotoxic chemotherapy.

Value is not cleared in the absence of RCT.

Good option in young and fit AML patients with high tumor burden.

Pre-HSCT therapy with DNA hypomethylating agents

• Widely used to prevent disease progression and to reduce transfusion needs while the process of donor selection is performed.

• Engraft graft-versus-MDS effects: increased expression of KIR and minor histocompatibility antigens .

• Patients who did not respond to HMA have very poor prognosis.

• Good outcome in TET-2 mutation

Pre-HSCT therapy with DNA hypomethylating agents

• Feasible, even in patients with comorbidities and or poor performance status

• Azacytidine: less toxicity than induction chemotherapy

• Lower response rates compare to induction chemotherapy

• no negative impact on HSCT outcome

Gerts AT et al : Biol Blood Marrow Transplant 2008; 14: 458-68Damaj G, et al: J Clin Oncol 2012; 30:4533-40

Type of treatment prior to transplantation: IC vs Aza

• 163 patients who underwent HCT after azacytidine(Aza), after AML-type induction chmeotherapy(IC), or after both.

• No differences in relapse rates, nonrelapse mortality, EFS, or overall survival comparing Aza and IC

Damaj et al J Clin Oncol 2012:30(36):4533-4540

Kaplan-Meier estimates of (A) 3-year overall survival, (B) 3-year event-free survival, (C) cumulative incidence of 3-year relapse, and (D) nonrelapse mortality (NRM) in 163 patients,

according to the prior-to-transplantation treatment received.

Damaj G et al. JCO 2012;30:4533-4540©2012 by American Society of Clinical Oncology

Pretransplatation therapy with Azacytidine vs Induction chemotherapy and Postransplantation Outcome in Patients with MDS

• Retrospective analysis: 68 patients who underwent allogeneic HSCT for MDS/AML transformed from MDS.

• Patients who received Aza were older than IC-treated patients(medain 60 vs 47years).

N 1-yr OS

post-HSCT mortality

Non-relapse mortality

relapse ratio

Aza 35 57% HR 0.68 HR 0.99 0.34

IC 33 36%

The risk of post-HSCT mortality , non-relapse mortality, and relapse were lower in the Aza-group compared to IC. After adjustment for cytogenetic risk, IPSS and donor, the rates for post-HSCT relapse for the 2 cohorts were similar.

Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218

Overall survival after HSCT according to pretransplantation therapy: Aza vs IC

P = 0.24


1-year OS: 57% vs 36%

Nonrelapse mortality following HSCT according to pretransplantation therapy: Aza vs IC


NS, p = 0.98

Relapse mortality following HSCT according to pretransplantation therapy: Aza vs IC

P = 0.04


Relapsed-free survival after HSCT according to pretransplantation therapy: Azacytidine vs IC

P = 0.14


Optimal time to consider proceeding to HSCT in MDS patients who are treated with

Azacytidine

- Benefit of Azacytidine therapy can be estimated according to the

“Aza prognostic score” using ECOG, PB blasts, Rbc-transfusion dependent and IPSS karyotype.

Considerations of when to proceed to an allogeneic HCT in a transplantation-eligible patient with higher-risk MDS in the context of

an anticipated prior treatment with AZA according to the AZA prognostic score.

Platzbecker U Hematology 2013;2013:522-528

Survival analysis according to the salvage treatment regimens.

Prébet T et al. JCO 2011;29:3322-3327©2011 by American Society of Clinical Oncology

(*) Univariate analysis (log-rank test) showed significant differences between palliative care and intensive chemotherapy (CT; P = .04), investigational therapy (IT; P < .001), or allogeneic stem-cell transplantation (ASCT; P < .001). (†)There was also a significant difference between intensive CT and IT (P = .05) and intensive CT and ASCT (P = .008). The difference between IT and ASCT reached borderline significance (P = .09).

Considerations for choosing the optimal treatment before allogeneic HCT in MDS

Platzbecker U Hematology 2013;2013:522-528

How we treat higher-risk myelodysplastic syndromes?

Mikkael Sekeres and Corey Cutler Blood 2014;123(60}; 829-836

Therapeutic algorithm for adult patients with primary MDS and Int-2 or high IPSS score

European LeukemiaNet Blood 2013;122(17):2943-2964

Conclusion• With the acceptable toxicity and potential

for cytoreduction, HMA including Azacytidine or Decitabine can be used as pretransplantation therapy.

• Induction chemotherapy is considered in young MDS patients with favorable and intermediate-karyotype, good performance status and high percentage of blasts.

• No pre-transplantation treatment is needed in MDS patients with

• co-morbidities, low blasts percentages.

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