FLT3,   General AML

Acute myeloid leukemia with t(6;9): a retrospective analysis of patient outcomes 

The World Health Organization (WHO) recognizes acute myeloid leukemia (AML) with the cytogenetic profile t(6;9)(p22,q34), as a distinct entity occurring in approximately 1–2% of cases.1,2 Often, an internal tandem duplication of FLT3 (FLT3-ITD) is also present. With chemotherapy, the outcomes of these patients, both adult and pediatric, is very poor with five-year overall survival (OS) rates as low as 9% in adult patients.2

In previous studies, allogeneic hematopoietic cell transplantation (allo-HCT) conducted early during first complete remission (CR1) has been reported to improve outcomes, but these results are limited in value due to a small sample size and missing data. As the outcomes of this subgroup are rarely reported in studies, Sabine Kayser, University Hospital Heidelberg, Heidelberg, DE, and colleagues designed a retrospective, international, multicenter study to better understand the responses of these patients, in order to inform future treatment strategies. The results were published in Haematologica in April 2019.3

Patient characteristics and study design
  • Patients with AML, t(6;9)(p22,q34) diagnosed between 1989 and 2016
    • N = 178
    • Median age: 46 years (16–76)
    • Type of AML:
      • De novo: 88%
      • Therapy related: 2%
      • Secondary after prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm: 7%
      • MDS treated with AML protocols: 3%
    • Cytogenetics:
      • In 79% (n = 140) of patients, t(6;9)(p22,q34) was the only abnormality
      • Other cytogenetic abnormalities were present in 21%
      • Of 127 patients for whom FLT3-ITD testing was available, FLT3-ITD was present in 62%
  • Of patients undergoing allo-HCT:
    • Conditioning regimens:
      • Myeloablative conditioning; n = 76 (with 39 receiving total body irradiation)
      • Reduced-intensity; n = 41
    • Donor source (matched related vs matched unrelated vs haplo-identical vs cord blood vs unknown): 46 vs 54 vs 11 vs 5 vs 1
  • Survival endpoints: OS, relapse-free survival (RFS), cumulative incidence of relapse (CIR) and cumulative incidence of death (CID)
  • Median follow-up: 5.43 years (95% CI, 3.93–6.53)
  • In the whole cohort:
    • Median OS was 2.25 years (95% CI, 1.56–3.70 years)
    • Five-year OS was 38% (95% CI, 31–47%)
Induction therapy

Of the 178 patients, 116 received intensive induction in a clinical trial setting and 62 received it according to the local standard. The most frequently used local standard was the 7+3 anthacycline + cytarabine regimen in 53/62 patients.

In total, 81% (n = 144) achieved a CR following induction therapy. Subgroup analysis showed that the presence of a FLT3-ITD did not influence CR (CR was 81% with FLT3-ITD and 77% without FLT3-ITD, P = 0.65). Early death occurred in 1% of patients (n = 2). No prognostic factors for CR were identified.

In 35 patients who failed to respond to initial induction treatment, salvage therapy was given (high-dose cytarabine [HiDAC]-based, other intensive, non-intensive, or unknown). Of these, 66% achieved a CR (n = 23). The authors observed that these patients were more sensitive to HiDAC and recommended this strategy should be investigated in this population.

Further therapy: consolidation versus allo-HCT

Patients achieving a CR1 (n = 144) then proceeded to either intensive consolidation chemotherapy (38%, n = 55) or allo-HCT (62%, n = 89). Consolidation therapy was given to 58% of patients prior to allo-HCT (n = 52). Outcomes to treatment during CR1 are shown in Table 1.

Table 1: Outcomes by treatment during CR1 (N = 144)

 

N

%

5-year RFS

95% CI

5-year OS

95% CI

Allo-HCT

89

62

45%

35–59

53%

42–66

Consolidation chemotherapy

55

38

7%

3–19

23%

13–38

Relapses subsequently occurred in 85% of patients (n = 47) after consolidation chemotherapy and 31% of patients (n = 28) after allo-HCT in CR1.

In total, 66% of patients received an allo-HCT (n = 117); 99 were performed during CR1 and 10 during CR2, while 18 patients received an allo-HCT with refractory or relapsed disease (refractory disease vs relapse; 15 vs 3). The outcomes of these patients were:

  • Allo-HCT during CR2 (n = 10):
    • Death; n = 6
    • Median time to death: 16.5 months post-allo-HCT
  • Allo-HCT with refractory disease (n = 15)
    • Death; n = 7 (median follow-up: 66.5 months)
  • Allo-HCT with relapsed disease (n = 3)
    • Death; n = 3
Outcome analysis

As shown in Table 2, the time of allo-HCT was not significantly associated with overall survival.

Table 2: Five-year OS by time of allo-HCT

 

5-year OS

95% CI

During CR1

53%

42–66

During CR2

58%

31–100

With active disease

54%

34–84

Table 3 shows an analysis of factors that may be associated with prognosis. In addition to the factors in Table 3, platelet count and type of AML were not found to have any impact on prognosis.

Table 3: Impact of factors on OS

Factor

P value

Conclusion

Presence of FLT3-ITD, total cohort

0.093

No prognostic impact on OS

Presence of FLT3-ITD, allo-HCT group

0.39

No prognostic impact on OS

Additional chromosomal abnormalities, total cohort

0.49

No prognostic impact on OS

Additional chromosomal abnormalities, allo-HCT group

0.86

No prognostic impact on OS

White blood cell (WBC) count

0.005

High WBC count - unfavorable

Age

0.001

An increase of 10 years - unfavorable

Conditioning regimen

0.90

No prognostic impact on OS

Donor type

0.30

No prognostic impact on OS

Status at transplant (CR1, CR2 or active disease)

0.66

No prognostic impact on OS

  • CIR was lower in patients achieving a CR1 who proceeded to allo-HCT vs consolidation chemotherapy; P < 0.001
  • CID was higher in patients receiving allo-HCT in CR1 vs consolidation chemotherapy; P = 0.08
Conclusion

In the subset of patients with t(6;9)(p22,q34), whose outcomes are rarely reported, this study has shown high CR rates after intensive induction therapy, indicating this should be the standard of care in this population, where possible.

However, since consolidation chemotherapy leads to poor outcome in this group, it is recommend that allo-HCT is performed during CR1. Whilst the best OS rates were seen in patients receiving allo-HCTs in CR1, a similar positive effect was seen in patients receiving allo-HCT during CR2 or those who had active disease, to a similar level as patients without adverse cytogenetics, indicating a strong graft-versus-leukemia effect.

Factors that one may hypothesize would influence OS, such as the presence of FLT3-ITD/additional cytogenetic abnormalities, decade of treatment, donor source and conditioning regimen, were not associated with OS. The authors highlighted one main limitation of this retrospective study, which was that the factors for allocating patients to allo-HCT are unknown.

References
  1. Swerdlow S.H. et al. WHO classification of tumours of haematopoietic and lymphoid tissues, revised 4th edition. WHO Press, Geneva, Switzerland, 2017
  2. Slovak M.L. et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia. 2006 Apr 20. DOI: 10.1038/sj.leu.2404233
  3. Kayser S. et al. Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia – results from an international collaborative study. Haematologica. 2019 Apr. DOI: 10.3324/haematol.2018.208678
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