What to do in minimal residual disease in acute lymphocytic leukemia?Maintenance TherapyDr. Raymond SM WongDepartment of Medicine & TherapeuticsPrince of Wales HospitalThe Chinese University of Hong Kong

Acute lymphoblastic leukemia (ALL)

• ALL is a heterogeneous disease affected by many patient- and disease-related factors, including age, immunologic subtype, and clinical, genetic, and molecular features

Lazarus HM, Advani AS, Hematology 2012

Acute lymphoblastic leukemia (ALL)

• Most children, adolescents and young adults with acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) have an excellent prognosis with multi-agent chemotherapy in induction, consolidation, re-induction and maintenance therapy

• There is a subset of patients with a more guarded prognosis using this approach, who may benefit from haematopoietic allogeneic stem cell transplantation (alloHSCT)

LALA-94 Comparisons of treatment

Thomas X, et al. JCO 2004, Khaled SK, et al. Curr Opin Oncol 2012

AlloSCT for high-risk ALL patients in CR1

Yanada M, et al. Cancer 2006

Allogeneic stem cell transplantation (AlloHSCT)

• AlloHSCT is the treatment of choice for patients with ALL after first relapse, and is also recommended for high-risk patients in first complete remission (CR1).

• There is no consensus on early transplant for standard risk patients

• The curative potential of alloHSCT must be balanced against the disadvantages (mortality of 20% to 30%, morbidity, late complications, reduced quality of life) and assessed in relation to the improved outcome by chemotherapy regimens

Minimal residual disease (MRD) and ALL

• MRD evaluation and monitoring is developing as an important prognostic factor

• May be used to improve risk stratification and to determine which patients, especially those with standard risk, might require alloHSCT

• MRD assessment may not be routinely available in all centers

Brüggemann M, et al. Blood 2006

AlloSCT versus Maintenance Chemotherapy

• ALL CR1 studies

Lazarus HM, et al. Hematology 2012

PETHEMA ALL-93 trial

• A total of 222 valid high-risk ALL patients recruited

• Patients in complete remission after induction chemotherapy (CR1) were assigned to alloHSCT (n = 84) if they had an HLA-identical family donor

• The remaining were randomized to • autologous SCT (n=50) or • delayed intensification followed by maintenance

chemotherapy up to 2 years in complete remission (n=48)

Ribera et al, Haematologica 2005

PETHEMA ALL-93 trial: disease-free survival

Ribera et al, Haematologica 2005

MRC UKALLXII/ECOG E2993 Study

• ALL in CR1

• N = 1031

• Age: 15 – 64 years

• AlloHSCT: 15-59 years

• 443 patients with donor

• 588 patients had no donor

Goldstone, et al. Blood 2008

MRC UKALLXII/ECOG E2993 Study

MRC UKALLXII/ECOG E2993 Study

Goldstone, et al. Blood 2008

MRC UKALLXII/ECOG E2993 Study

Goldstone, et al. Blood 2008; Khaled, et al. Curr Opin Oncol 2012

HOVON Studies

• Newly diagnosed patients with precursor B-cell or precursor T-cell ALL included in the HOVON-18 ALL (HO18) and HOVON-37 ALL (HO37) studies between November 1992 and November 2005

• myeloablative alloHSCT in CR1 patients aged 15-55 years

• N = 257

• Donor = 96

• No donor = 161

Comelisson et al, Blood 2009

HOVON Studies: DFS

Comelisson et al, Blood 2009

HOVON Studies: OS

Comelisson et al, Blood 2009

HOVON Studies: Outcomes

Comelisson et al, Blood 2009

Findings of recent studies

• Survival benefits appears to be greater for patients with standard-risk rather than high-risk ALL patients.

• In the older randomized trials and a meta-analysis, high-risk rather than standard-risk patients benefited from alloHSCT

• Age as a high-risk feature accounts for much of the data showing that the standard-risk group benefited the most

• Likely reflects the increased treatment-related mortality (TRM) in the high-risk group that negated the GVL effect in these patients

• Inclusion of the younger patients in the recent randomized trials, may have biased the results in favor of alloHSCT

Summary

• ALL is a heterogenous disease and management should be tailored for each patient

• The benefits of alloSCT in high risk patients appeared conflicting in various studies

• The risk in transplant related mortality needs to be carefully balanced against the disease free survival benefit

• There is a dilemma when a patient has standard risk for relapse especially when MRD assessment is not available

• Maintenance chemotherapy is still an options in patients with ALL in CR1

The EndThank you