Continuing Challenges and Current Issues in Acute Lymphoblastic Leukemia

DR. MENOTI PAUL MUKTI

RESIDENT, HEMATOLOGY

PHASE B, BSMMU

INTRODUCTION

ALL has a bimodal distribution-

-First presentation in 5 years of age

-Second peak around the age of 50 years

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5 year survival rate

-around 90% in children

-only 30-40 % in adults

Cont:

Factors affecting disease prognosis and outcome in adult-

-Age at presentation

-Unfavorable cytogenetics

-Poor tolerance to high dose chemotherapy

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Outcome of adult ALL is advanced by understanding-

-New cytogenetics and molecular abnormalities

-novel targeted agents ( TKI, Monoclonal antibody, novel immunotherapy)

Age distribution in childhood and adult ALL

Age based risk distribution in childhood and adult ALL

To face the challenges in adult ALL treatment , here seven key areas are discussed-

1. The role of minimal residual disease (MRD) monitoring in ALL

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2. Treatment of adolescents and young adults with ALL

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3. Advances and challenges in the treatment of older adults with ALL

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4. Monoclonal antibodies in the treatment of ALL

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5. The role of chimeric antigen receptor T cells (CART) in ALL

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6. The utility of hematopoietic stem cell transplantation (HSCT) in ALL

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7. Treatment of Philadelphia positive (Ph.) ALL in era of tyrosine kinase inhibitors (TKIs).

The role of minimal residual disease (MRD) monitoring in ALL��

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MRD is one of the most powerful predictors of disease free and overall survival for patients with ALL

Available techniques are-

Polymerase chain reaction ( PCR)

Multicolour flow cytometry

Deep sequencing

Best test to measure MRD

Comparison of two commonly used method of MRD testing

Ideal source of cells for MRD analysis

Sources-

Bone marrow aspirates

peripheral blood

In T-ALL-

Blood MRD were comparable to or up to 1 log lower than bone marrow MRD

In B-ALL-

Blood MRD levels were 1-3 logs lower than bone marrow MRD level

So bone marrow is the preferred method

Time for MRD assessment

Timing for MRD assessment in adults varies depending on the various treatment regimens

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Can be done

- after end of induction and or

-during consolidation therapy

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Commonly accepted that initial measurement should be performed after completion of induction in ALL

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Decisions to intensify or de- intensify treatment after MRD

Chemoimmunotherapy combination trials in ALL

Treatment of adolescent and young adults�

Defined as 15 – 39 years

Poor prognosis with EFS 30-45%

Reasons-

Heterogenecity of disease biology

Therapeutic approach

Higher disease relapse-CNS

Decreased compliance with long, complex treatment regimens

Principles of pediatric protocols-

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- use of 7–8 drugs with dose intensity of less myelosuppressive agents

- use of prolonged post-remission asparaginase (ASP)

- delayed re-induction

- early CNS prophylaxis during induction and

- restricting allo-HSCT for very high-risk patients

Principles of adult protocols-

- More intensive myelosuppressive agents

- allo-HSCT in first remission

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Study shows that AYAs have superior outcomes when treated with pediatric inspired protocols with 5 year EFS 60-70% compared to 30-40% with adult protocols

Trials of pediatric and pediatric inspired regimens in adult ALL

Advances and challenges in treatment of older adults

Protocols for older ALL patients have focused-

To provide a chance for remission

Prolonged survival

Minimize toxicites

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To reduce the toxicity various new approaches are being evaluated

• In BFM- based dose reduced approach-

omission of ASP

Reduced dose of anthracycline

CR was 76%

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• Utilization of TKI as upfront treatment

Imatinib 800 mg and prednisolone for induction followed by imatinib single drug treatment

Remission rate was 100 % at 1 year

By using Dasatinib 140 mg CR was 92%

• Use of monoclonal anti bodies-

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Inotuzumab ozagamicin combined with mini HCVD

CR was 83%

attractive option for elderly ALL

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• Blinatumomab as upfront therapy

In ph- ALL

blinatumomab induction with POMP

In PH+ ALL

dasatinib with prednisolone followed by blinatumomab and dasatinib

Role of CAR –T cells in ALL

The majority of CAR-T constructs have used CD19 antibody to target CD 19 expressing cell

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All B –ALL -Both malignant and non malignant express this molecule as a cancer antigen

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Highly innovative for relapse and refractory ALL

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Used as a bridge to transplant

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In relapsed B ALL-

By using this therapy MRD negative CR was 60-90% where by adding Blinatumomab CR was only 43%

Toxicities of CAR-T cell-

Cytokine release syndrome

Neurotoxicity

B cell aplasia

For this toxicities the use of this is challenging and limited to specialized centre

Monoclonal antibodies in ALL

• Use- Relapse and refractory ALL

Elderly ALL

MRD positive B-ALL

• Primarily targated against CD19, CD20, CD22, CD52
• Aim to effect anti tumor activity with minimization of toxicity
• Can be used as a single agent or in combination with chemotherapeutic agents

• Type-

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Non conjugated form- Target single antigen on tumor cell

Exm-CD20 with Rituximab and Ofatumumab

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Conjugated form with cytotoxic agents

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Exm CD22 with inozumomab

CD19 with Denintuzumab

Bispecific TCR engager-

Blinatumomab –has both monoclonal antibody against CD 19 and CD 3

Type of monoclonal antibodies

Mechanism of action of monoclonal antibodies

The utility of HSCT in ALL

With the advance treatment CR in adult ALL is improved by 75-90% but due to high relapse rate the long term survival rate only 25-50%

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Here the question of all-HSCT in first CR is arised in adult

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OS is more pronounced in standard risk group than the high risk

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Relapse rate is more responsive to all- HSCT in standard risk group than high risk

Conditioning regimen before allo-HSCT

Comparing between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) –

It is observed that OR with RIC is 66% at 22 month suggesting it is a valid option for patients >40 years of age

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RIC may even turn out to be superior to MAC regimens

Treatment of ph+ALL in era of TKI

• Before the development of TKI the philadelphia positivity reffered as a poor prognosis (OS was 20%)

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Then allo- HSCT to all patient in first remission was standard practice

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• After introduction of Imatinib in ph+ ALL the CR is improved to 90%

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With the improvement in therapy with TKI in post remission the role

of allo-HSCT in CR1 is beginning to be debated

Contd:

• Multiple trial to assess the survival benefit between post induction allo-HSCT and chemotherapy alone with TKI is done

• It revealed that who did not received transplant have slightly inferior outcome than the transplant group

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• Sugesting that patient can still do quite well when they are not able to receive transplant

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• In another study with nilotinib, they suggest if patient achieve a CMR transplant may not be needed

Contd:

• Choice of TKI –

current evidence suggest second generation TKI have superior potency and wider activity

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• Role of transplantation –

needs to be individualized,

current standard of care remains transplant for tranplant eligible patient

Conclusions�

• Significant development –

-newer therapy

-better assessment of MRD

-Improved risk stratification

-improved survival with reduced toxicity

• Improved survival and reduce relapse –

-adding monoclonal antibody,TKI, CAR T cell therapy

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Contd:

• Recommendation-

allo-HSCT remains the standard of care for transplant eligible patients including ph+ALL

Elderly pt with ALL- inotuzumab to low intensity chemotherapy improve outcome

The challenges for us

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Identify specific subgroup of ALL patients

Focus on individualized approach

Maintain a balance between medical and financial toxicity and improving patient outcomes

Thank you