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Prognostic Markers and Models in Acute Lymphoblastic Leukemia

Dieter Hoelzer

University of Frankfurt, Germany

Introduction

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease characterized by subgroups with different biological and clinical features and cure rates. They have prognostic impact for the achievement of remission or the remission duration. There are two phases to evaluate prognostic factors: (1) Patient's characteristics at diagnosis, and (2) patient's response to treatment (Table 1.1). Pretherapeutic prognostic features are age, initial white blood cell (WBC) count, immunophenotype, and abnormal cytogenetics or molecular genetics. Response parameters are achievement of complete remission, particularly molecular remission, and time to achieve a complete remission and molecular remission. The aim of evaluating prognostic factors in ALL is to stratify patients into good and poor risk groups and to adapt different treatment strategies accordingly. One important decision in adult ALL is, thereby, whether a patient should have an allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission or not.

Table 1.1 Prognostic factors for risk stratification of adult acute lymphoblastic leukemia (ALL)1.

• Age

> 55-60 years

> 70 years elderly/frail

• White blood cell count

• Organ involvement3

• Immunophenotype

Early T (CD1a-, sCD3-)

Mature T (CD1a-, sCD3+)

• Molecular/subgroups cytogenetics

Ph+/BCR-ABL1 t(9;22)(q34;q11.2)

IgH-MYC+, t(8,14)(q24;q32)

TEL-AML1 (?)

HOX112

NOTCH12 (?)

-Deletion

7p focal deletions/ mutations

MLL rearranged

Ph-like

ALL1-AF4 / t(4;11)

t(1;19)/E2A-PBX (?)

Complex aberrations (?)

HOXA aberrations

CALM-AF10

Complex aberrations (?)

1Generally accepted factors are printed in bold.

2Overexpression of genes.

3Organ involvement, particularly central nervous system involvement, and mediastinal tumors have lost their adverse impact with recent treatment strategies.

4MRD, measurable residual disease.

• 1) What is the prognostic value of patient's age at diagnosis in adult ALL, and what are the therapeutic implications?

Expert Perspective: Advancing age is undoubtedly associated with poorer outcome in all studies. In adolescents and young adults (AYAs, i.e. adults up to age 40), pediatric-inspired intensive protocols are applied. Thereafter, the protocol intensity is decreased. Currently, treatment protocols for elderly (> 60 years) are with less intensive chemotherapy backbone combined with immunotherapies and/or with tyrosine kinase inhibitors (TKIs) in Ph+ ALL (discussed in chapters on treatment in B- and T-ALL). Patients older than age 60 years have a substantially poorer outcome due to comorbidities and an increasing incidence of adverse risk factors. All patients are subject to CNS screening by flow cytometry and prophylaxis.

• 2) Does WBC at diagnosis still have a prognostic impact in B-ALL and T-ALL?

Expert Perspective: Elevated WBC at diagnosis (> 30,000-50,000/mL) is a poor prognostic feature, especially deleterious in precursor B-cell ALL. Subtype Ph-like ALL (provisional category 2016 WHO classification) has higher WBC count at presentation, higher measurable residual disease at the end of induction therapy and inferior overall survival (Chapter 2). In T-ALL a high WBC > 100,000 was considered a poor prognostic factor but with an ongoing more-intensive protocol these adverse factors seem to be abrogated (Chapter 3).

• 3) What is the relevance of cytogenetic and molecular markers for treatment decisions?

Expert Perspective: Ph+ ALL with the t(9;22) translocation and the BCR-ABL fusion transcript is the most prevalent cytogenetic abnormality in adults with B-ALL, increasing from < 3% in children up to 40-50% in adults over the age of 50-60 years. Ph+ ALL was so far the poorest ALL subtype, with a survival rate at 5 years of < 10% with chemotherapy and < 30% with allo-HCT. Targeted therapy with tyrosine kinase inhibitors (TKIs) in combination with chemotherapy has changed the prognosis landscape dramatically; now the complete remission rates approach levels > 90% and survival > 50-70% in most series. Allo-HCT is still a curative approach with a survival rate of 50-70% for ALL.

• 4) Which of the following statements about Ph-like ALL is correct?
  1. It is more common in adults than in children.
  2. It is associated with superior outcomes without allogeneic transplant.
  3. There is no role of JAK-2 inhibitor therapy in B-ALL.
  4. All of the above.

Expert Perspective: Ph-like ALL is characterized by a gene-expression profile like that of BCR::ABL1-positive ALL but lacks the BCR::ABL1 fusion protein, or t(9;22), by cytogenetic, FISH, or molecular analysis and alterations of lymphoid transcription factor genes. It is associated with poor prognosis and is seen in 10-20% of pediatric cases and 20-30% of adult cases of B-ALL. It is included as a provisional entity in the 2016 WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive targeted therapy added to conventional chemotherapy, one of them being JAK-2 inhibitor therapy (more on this topic in Chapter 2).

Tyrosine Kinase Rearrangements

A feature of Ph-like ALL is the presence of fusion genes involving a tyrosine kinase: the ABL-class and JAK2 arrangements. In adolescents and adults, ABL-class rearrangements occur in about 10% and JAK2 rearrangements are detected in 7-8%. Patients with ABL-class rearrangements should receive additional TKI therapy. Patients with JAK2 rearrangements may be candidates for additional JAK2-inhibitor therapy.

Diagnosis of Ph-like ALL

Diagnosis of a Ph-like ALL is difficult. There are low density classifiers (LDA) to identify predictor genes assays of either 8 or 9 gene signatures. Since the diagnosis of Ph-like ALL is not trivial and is not available at first diagnosis, commonly specific drugs are added later. There are, however, studies to identify Ph-like ALL genetics stratification at diagnosis as in the COG trial (Chapter 2).

Ph-like ALL has poor prognosis, and patients often present with adverse features such as high WBC. These patients should be considered for frontline allo-HCT. Whether the addition of immunotherapy as in Ph+ ALL improves the poor outcome of Ph-like ALL remains an open question (Chapter 5).

Correct Answer: A

• 5) In current clinical practice, what are the targetable surface antigens in B-ALL?

Expert Perspective: A variety of targeted monoclonal antibody therapies directed against surface antigens, particularly CD20 (rituximab and other anti-CD 20 antibodies), CD19 (blinatumomab and chimeric antigen receptors T cells), and CD22 (inotuzumab ozogamicin). These targeted antibodies have been and are further being explored (Chapter 2).

• 6) What is the prognostic value of CD20, CD22, and CD19 surface expression in B-ALL?

Expert Perspective: The question arises of whether antigen expression itself within an immunologically defined subtype is a prognostic marker.

• Surface CD20 expression, observed in about 40% of adult pre-B-ALL and common B-ALL, had an adverse prognostic impact, but the therapy with rituximab has apparently overcome the potential adverse...