Should patients with refractory anemia with excess blasts or those with oligoblastic AML receive induction therapy prior to allogeneic transplantation?
Yes: Suporn Chancharunee, MD
No: Nina Shah, MD
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oligoblastic AML
1. Should patient with refractory
anemia with excess blasts or
those with oligoblastic AML
receive induction therapy prior
to allogeneic transplantation?
2. Should patient with refractory
anemia with excess blasts or
those with oligoblastic AML
receive induction therapy prior to
allogeneic transplantation?
My answer is“Yes”
3. Should patient with refractory anemia
with excess blasts or those with
oligoblastic AML receive induction
therapy prior to allogeneic
transplantation?
My answer is “Yes”
What is the evidence-based data?
No randomized trials and retrospective
studies are subject to selection bias
4. 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
7. 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
8. The only curative treatment modality for high
risk MDS is allogeneic hematopoietic cell
transplantation(HSCT)
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
9. 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
10. Type of treatment prior to
transplantation
• AML induction-type chemotherapy
• Hypomethylating agent(HMA) therapy
11. 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
12. Outline
• Terminology: RAEB-t , Oligoblastic AML
• Type of induction therapy prior to HSCT
• Does the disease burden at the time of HSCT
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
Recommendations from the experts
13. 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.
14. 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
15. 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: 458-68
Damaj G, et al: J Clin Oncol 2012; 30:4533-40
16. 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
18. 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).
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.
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%
Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218
19. Overall survival after HSCT according to
pretransplantation therapy: Aza vs IC
P = 0.24
1-year OS: 57% vs 36%
Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218
20. Nonrelapse mortality following HSCT according to
pretransplantation therapy: Aza vs IC
NS, p = 0.98
Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218
21. Relapse mortality following HSCT according
to pretransplantation therapy: Aza vs IC
P = 0.04
Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218
22. Relapsed-free survival after HSCT according to
pretransplantation therapy: Azacytidine vs IC
P = 0.14
Gerts AT et al : Biol Blood Marrow Transplant 2012; 18: 1211-1218
23. 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.
24. 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
26. 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
27. Considerations for choosing the optimal treatment before
allogeneic HCT in MDS
Platzbecker U Hematology 2013;2013:522-528
28. How we treat higher-risk myelodysplastic syndromes?
Mikkael Sekeres and Corey Cutler Blood 2014;123(60}; 829-836
29. Therapeutic algorithm for adult patients with
primary MDS and Int-2 or high IPSS score
European LeukemiaNet Blood 2013;122(17):2943-2964
30. 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.
Notes de l'éditeur
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. AZA, azacitidine; HR, hazard ratio; ICT, induction chemotherapy; ns, not significant.
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.21 The benefit of a therapy with single-agent AZA can be estimated according to the AZA prognostic score. As a result, one might estimate the optimal time point of when to consider proceeding to allogeneic HCT in a transplantation-eligible patient. Several trials with AZA have shown that at least 80% of patients achieved their best response after only 6 cycles of treatment. This means that only a minority of patients can further deepen their magnitude of response (eg, from partial to complete response) by the administration of additional cycles. Therefore, the continuation of AZA is considered to preserve the response already achieved at this time point. Patients with an AZA score of ≥ 1 have, in general, a high likelihood to lose their response early, even in the presence of a subsequent continuation of AZA. Therefore, I suggest limiting exposure to AZA in this group of patients in cases in which a donor has been already identified. OS indicates overall survival; PB, peripheral blood; and ECOG, Eastern Cooperative Oncology Group performance status.
Survival analysis according to the salvage treatment regimens. Overall response rate for each treatment group is presented with the number of patients evaluable for response in each cohort. (*) 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). AZA, azacitidine; NA, not applicable; ORR, overall response rate; OS, overall survival.
Considerations for choosing the optimal treatment before allogeneic HCT in patients with MDS. In general, there are 3 potential treatment options for transplantation-eligible patients before allogeneic HCT. The figure provides some rationale for choosing the optimal therapy before a planned transplantation. PD indicates progressive disease. 1Donor already identified. 2In general, IC can achieve higher complete response rates than AZA irrespective of karyotype abnormalities. The recommendation above is based on the fact that patients with a poor-risk karyotype have a lower chance to respond to IC than patients with normal cytogenetics (∼ 40% vs 70%). In patients with poor-risk karyotype and no identified donor, a soft “bridging” (although with a lower chance of response than with IC) that avoids the immediate toxicities of IC might be a reasonable alternative. Alternatively, patients with a good-risk karyotype have a good chance of responding to IC, which might therefore be considered as an option even in the immediate absence of a compatible donor.