POST-INDUCTION MRD PREDICTS HIGH RELAPSE RISK FOLLOWING REDUCED INTENSITY CONDITIONED ALLOGENEIC STEM CELL TRANSPLANTATION: A PROSPECTIVE STUDY OF ADULT ALL (UKALL14,ISRCTN 66541317)
(Abstract release date: 05/18/17)
EHA Library. Okasha D. 06/25/17; 182089; S802
Dina Okasha
Contributions
Contributions
Abstract
Abstract: S802
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00
Location: Room N103
Background
Reduced intensity conditioned allogeneic haematopoietic stem cell transplant (RICalloHCT) enables HCT to be performed in older patients. The UK NCRI UKALL14 study of adult acute lymphoblastic leukaemia (ALL) considers patients ≥41 years “high risk” and recommends a RICalloHCT where there are high quality donors. Other “high risk” factors are high WBC at presentation, t(9;22), t(4,11), hypodiploidy/near triploidy, complex karyotype and positive minimal residual disease (MRD) after completing induction therapy. The presence of MRD at this time-point predicts poor outcome after conventional chemotherapy. There is evidence that myeloablative alloHCT can overcome this risk, but the benefit of RICalloHCT is uncertain.
Aims
To determine whether RICalloHCT mitigates the high relapse risk predicted by MRD positivity after induction therapy.
Methods
Protocol treatment: patients receive a steroid pre-phase before 2 cycles of induction chemotherapy. At the end of induction, patients are assigned subsequent therapy on the basis of risk. All patients over 41 years are allocated RICalloHCT, conditioned with fludarabine, melphalan and alemtuzumab. Post HCT, escalating doses of donor lymphocyte infusions were given for T-cell mixed chimerism +/- MRD persistence or relapse. MRD assessment: BCR/ABL1 or Ig/TCR MRD was assessed and analysed per EuroMRD guidelines. MRD is negative (undetectable with an assay quantitative range of 1x10-4 or less), positive (>1x10-4), positive outside quantitative range (POQR)(<1x10-4) or indeterminate (undetectable but assay quantitative range >5x10-4). Patients with indeterminate MRD were excluded from this analysis.
Results
There are 736 patients randomised to date, of whom 184 received a RICalloHCT; of these, 115 had analysable MRD. The following table shows patient characteristics.
| Patient characteristics | n=115 | Disease characteristics | n=115 |
| Age at randomisation median (range) | 49 (30-65) | B-ALL | 100 (87) |
| Presenting WBC median (range) | 8.6 (0.1-557) | T-ALL | 15 (13) |
| Sex N (%) | High-risk cytogenetics N (%) | ||
| Male | 61 (53) | BCR/ABL1 N (%) | 39 (33.9) |
| Female | 54 (47) | t(4,11) | 6 (5.2) |
| Donor type N (%) | Hypodiploidy/near triploidy | 7 (6.1) | |
| Sibling | 40 (34.8) | Complex karyotype | 3 (2.6) |
| Matched unrelated | 75 (65.2) | UKALL14 cytogenetic risk group N (%) | |
| Post induction MRD N (%) | Standard | 42 (36.5) | |
| Negative/POQR | 77 (67) | High risk | 53 (46.1) |
| Positive | 38 (33) | Unknown | 20 (17.4) |
At 2 years post transplant, overall survival (OS) was 63.1% in the 115 patients with evaluable MRD and 62.7% in the 184 patients receiving RICalloHCT; event free survival (EFS) was 55.2% and 55.9% respectively. By contrast, in the 38 of 115 patients with positive MRD after induction, OS and EFS were 40.6% and 28.4% respectively.
Twenty eight of the 115 patients relapsed, with a 2 year actuarial relapse risk of 31.5% (22.2-43.5). We assessed the association of the following factors; age, sex, immunophenotype, presenting WBC, BCR/ABL1, other cytogenetics, post-induction MRD and donor type with the risk of relapse. Among this population of high risk patients, post-induction MRD was the only independent prognostic factor for relapse (univariable HR: 3.82 (1.59–9.16), p 0.001 (see figure) and multivariable HR: 4.14 (1.61-10.65), p= 0.003). The relapse rate of the MRD+ patients was 57.2% at 2 years post HCT.
Conclusion
The 2-year OS of 62.5% in UKALL14 participants over 41 years old after RICalloHCT is greater than would be expected with chemotherapy alone. However, MRD positivity after induction is associated with significantly lower OS, EFS and a higher risk of relapse, which is not abrogated by RICalloHCT.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Reduced intensity transplantation, Minimal residual disease (MRD), Allogeneic hematopoietic stem cell transplant, Acute lymphoblastic leukemia
Abstract: S802
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00
Location: Room N103
Background
Reduced intensity conditioned allogeneic haematopoietic stem cell transplant (RICalloHCT) enables HCT to be performed in older patients. The UK NCRI UKALL14 study of adult acute lymphoblastic leukaemia (ALL) considers patients ≥41 years “high risk” and recommends a RICalloHCT where there are high quality donors. Other “high risk” factors are high WBC at presentation, t(9;22), t(4,11), hypodiploidy/near triploidy, complex karyotype and positive minimal residual disease (MRD) after completing induction therapy. The presence of MRD at this time-point predicts poor outcome after conventional chemotherapy. There is evidence that myeloablative alloHCT can overcome this risk, but the benefit of RICalloHCT is uncertain.
Aims
To determine whether RICalloHCT mitigates the high relapse risk predicted by MRD positivity after induction therapy.
Methods
Protocol treatment: patients receive a steroid pre-phase before 2 cycles of induction chemotherapy. At the end of induction, patients are assigned subsequent therapy on the basis of risk. All patients over 41 years are allocated RICalloHCT, conditioned with fludarabine, melphalan and alemtuzumab. Post HCT, escalating doses of donor lymphocyte infusions were given for T-cell mixed chimerism +/- MRD persistence or relapse. MRD assessment: BCR/ABL1 or Ig/TCR MRD was assessed and analysed per EuroMRD guidelines. MRD is negative (undetectable with an assay quantitative range of 1x10-4 or less), positive (>1x10-4), positive outside quantitative range (POQR)(<1x10-4) or indeterminate (undetectable but assay quantitative range >5x10-4). Patients with indeterminate MRD were excluded from this analysis.
Results
There are 736 patients randomised to date, of whom 184 received a RICalloHCT; of these, 115 had analysable MRD. The following table shows patient characteristics.
| Patient characteristics | n=115 | Disease characteristics | n=115 |
| Age at randomisation median (range) | 49 (30-65) | B-ALL | 100 (87) |
| Presenting WBC median (range) | 8.6 (0.1-557) | T-ALL | 15 (13) |
| Sex N (%) | High-risk cytogenetics N (%) | ||
| Male | 61 (53) | BCR/ABL1 N (%) | 39 (33.9) |
| Female | 54 (47) | t(4,11) | 6 (5.2) |
| Donor type N (%) | Hypodiploidy/near triploidy | 7 (6.1) | |
| Sibling | 40 (34.8) | Complex karyotype | 3 (2.6) |
| Matched unrelated | 75 (65.2) | UKALL14 cytogenetic risk group N (%) | |
| Post induction MRD N (%) | Standard | 42 (36.5) | |
| Negative/POQR | 77 (67) | High risk | 53 (46.1) |
| Positive | 38 (33) | Unknown | 20 (17.4) |
At 2 years post transplant, overall survival (OS) was 63.1% in the 115 patients with evaluable MRD and 62.7% in the 184 patients receiving RICalloHCT; event free survival (EFS) was 55.2% and 55.9% respectively. By contrast, in the 38 of 115 patients with positive MRD after induction, OS and EFS were 40.6% and 28.4% respectively.
Twenty eight of the 115 patients relapsed, with a 2 year actuarial relapse risk of 31.5% (22.2-43.5). We assessed the association of the following factors; age, sex, immunophenotype, presenting WBC, BCR/ABL1, other cytogenetics, post-induction MRD and donor type with the risk of relapse. Among this population of high risk patients, post-induction MRD was the only independent prognostic factor for relapse (univariable HR: 3.82 (1.59–9.16), p 0.001 (see figure) and multivariable HR: 4.14 (1.61-10.65), p= 0.003). The relapse rate of the MRD+ patients was 57.2% at 2 years post HCT.
Conclusion
The 2-year OS of 62.5% in UKALL14 participants over 41 years old after RICalloHCT is greater than would be expected with chemotherapy alone. However, MRD positivity after induction is associated with significantly lower OS, EFS and a higher risk of relapse, which is not abrogated by RICalloHCT.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Reduced intensity transplantation, Minimal residual disease (MRD), Allogeneic hematopoietic stem cell transplant, Acute lymphoblastic leukemia
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