Treatment and Management of Adult B-Cell Acute Lymphoblastic Leukemia in Asia

Introduction

Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid cells (B and T-cells), characterized by a rapid expansion of immature lymphocytes in the blood. It is usually induced by genetic abnormality, such as mutation and chromosomal alterations, affecting lymphoid development and cell cycle.

From the two subtypes, B-cell ALL is the predominant one with nearly 80% of all ALL cases. It is the most common leukemia in children, representing 25% of all cancers during childhood and a high long-term survival rate (90%). It is also common in adults but with a significantly lower survival rate (35-45%) compared to children.

Prevalence and incidence of B cell ALL in Asia

Globally, the incidence of acute lymphoblastic leukemia is estimated to be 1-4.75 per 100,000 people and represent 12% of all leukemia cases.

In adults, ALL is the second most common type of acute leukemia. It constitutes around 20% of adult acute leukemia. Among this, the B-cell phenotype is most common (~75%), followed by the T-cell (~24-40%) and mixed type (both B and T lineage, ~8-13%).

International incidence rate: Generally higher in America and Oceania and lower in Eastern Europe and Asia.

South Asia: According to a cross-sectional study conducted in South Asia in 2020, there were 62,163 leukemia-related cases out of 1,733,573 cancer cases documented that year.

India: As per the 3-year report from the National Cancer Registry Program in India, the incidence of lymphoid leukemia ranged from 0.2-14.8 per 100,000 people.

Children vs adults: The incidence rate of ALL in children is approximately four times that in adults in most countries.

Male vs female ratio: The incidence rate has been observed to be higher in males than females.

Predisposing factors of ALL:

Genetic susceptibility

• Congenital syndromes: Down’s syndrome, Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, Nijmegen breakage syndrome

• Inherited gene variants: ARID5B, IKZF1, CEBPE, CDKN2A/CDKN2B, PIP4K2A, ETV6

• Constitutional Robertsonian translocation between chromosomes 15 and 21

• Single nucleotide polymorphisms: rs12402181 in miR-3117 and rs62571442 in miR-3689d2

Environmental factors

• Pesticide exposure

• Ionizing radiation

• Childhood infections

Figure 1: Proposed protocols for adults with ALL in countries with varying resources

Limitations and unmet needs that affect optimal treatment outcomes among adult B-cell ALL in Asia

The unfavorable risk factors that leads to inferior responses and negatively affects optimal outcomes include:

• Age 35 years or older. Adults with ALL present with adverse risk features more often

• High leukocyte count (>30 × 10⁹ cells per L for B-cell acute lymphoblastic leukemia)

• Unfavorable cytogenetics: Philadelphia positive, [t(9;22)]) and KMT2A (MLL) gene rearrangement (chromosome 11q23)

• Older age at diagnosis. There is a significant association between an increase in age and worsening survival (p <0.001)

• Poor tolerance to intensive chemotherapy that causes delays in the planned treatment and optimal dosing

• A poorer minimal residual disease (MRD) response

• The treatment-intensive protocols and the resulting toxicity are also a barrier to delivering desired intensive therapy

• Limited resources availability to manage treatment-related toxicities such as subsequent infections and prolonged cytopenia

• Insufficient adoption of pediatric protocols by adult centers

• Decreased adherence to dose intensity, especially during the maintenance phase

• Reducing the dosage of essential drugs such as L-asparaginase

• Variations in psychosocial care

Patient outcomes for B cell ALL in Asia

At present, the 5-year survival rate in children is about 90% and 75-85% in adolescents and young adults. However, the survival outcomes in older adults are poor, with an overall survival rate of 35-55% in middle age adults and below 30% in patients over the age of 60.

Although conventional chemotherapy in adults has been shown to achieve 80 to 90% remission rates, the relapse rates are much higher.

In a few clinical trials, the adaptation of pediatric treatment regimens in adult patients has shown an improvement of around 50% in the improved 5-year survival.6

A study in North India - The B-cell ALL group showed better prognosis compared to T-cell ALL. The cALLa antigen positive B-cell cases achieved higher number of complete remissions and less relapses.

Differences in the protocols used:

Protocol	Complete remission (CR)	Maintained CR	Overall survival rate
UKALL-XII	58.6%	41.4%	71.4%
Modified BFM 90	84.2%	71.1%	78.9%
Pediatric BFM*	87.5%	92.3%	-

*Only a minority of patients were in this group and were of low-risk category.

Efficacy of immunotherapy agents

Considerable advancements have been made in understanding the pathophysiology of ALL over the last decade, and development of immunotherapy has helped in evolution of the treatment.

There are four types of immunotherapies developed so far:

1. Naked monoclonal bodies: rituximab, epratuzumab, and alemtuzumab

2. Conjugated monoclonal bodies: inotuzumab ozogamicin, SAR3419, and SGN-CD19A

3. Bispecific T cell engager: blinatumomab

4. Chimeric antigen receptor (CAR) T cell therapy

Based on therapeutic targets:

1. Anti-CD19 monoclonal antibodies (mAB): SGN-CD19A and blinatumomab

2. Anti-CD20 mAB: rituximab, ofatumumab, and obinutuzumab

3. Anti-CD22 mAB: epratuzumab, BL22, moxetumomab pasudotox, and inotuzumab ozogamicin

4. Chimeric antigen receptor-modified T cells and natural killer cells: targets and mechanisms of action

Figure 2: Different mechanisms of immunotherapies treating ALL

Rituximab Targets CD20	At a cancer center, Ph-negative B ALL patients were treated with the modified regimens of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) with or without rituximab. In the age subgroup <60 years, complete remission duration (CRD) and overall survival (OS) were superior with the hyper-CVAD and rituximab combination compared with hyper-CVAD alone (69 vs. 38%, P <0.001 and 71 vs. 47%, P = 0.003, respectively). However, no such benefits were observed in the age group >60 years.
Ofatumumab 2nd-generation anti-CD20 mAb	It is more potent than rituximab in inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and has mild adverse effects. In a phase II trial of hyper-CVAD/MTX-Ara-C in combination with ofatumumab for adults with CD20-positive ALL, 98% of patients achieved a CR after cycle 1, and 53 patients (93%) achieved minimal residual disease (MRD) negativity. The CRD and OS rates of 3-years were 78 and 68%, respectively.
Chimeric antigen receptor (CAR) T cells CD19-directed	CAR T cells recognize unprocessed antigens and are activated in a major histocompatibility complex-independent manner. In 53 adult patients with ALL, complete remission was achieved in 83% of patients (73% being minimal residual disease negative), having 6.1 months of event-free survival and 12.9 months of overall survival.
Blinatumomab CD3/CD19-directed (bispecific T-cell engager)	In a multicenter, open-label, China registrational study in adult patients with Ph-negative relapsed/refractory (R/R) BCP-ALL, CR rate with 2 cycles of blinatumomab was 45.6%. Median overall survival was 9.2 months and median relapse-free survival was 4.3 months. Similar results were observed in a post hoc pooled analysis in Japanese adults.
Inotuzumab ozogamicin (INO) Targets CD22	In a phase II study, 49 patients with R/R ALL were treated with 1.8 mg/m2 INO every 3 to 4 weeks as a single agent. It resulted in an ORR of 57% (18% CR and 39% CRi) and median OS of 5.1 to 7.9 months in all patients. In a subgroup analysis, 55 Asian patients were randomized (31 INO and 24 standard of care). CR or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO vs. 5/24 treated with standard of care.

Immunotherapy brings forth a new method towards the treatment of ALL patients. It can expand as conventional chemotherapy which can be further optimized via rational targeted approaches. This could eventually help in reducing rates of toxicity, death, and serious late complications for patients with refractory or recurrent disease.

Immunotherapies could substitute chemotherapy or contribute in lowering the dose of chemotherapy and achieve long-term remission in ALL patients.

Conclusion

A desired approach in the management of ALL in Asian countries is the adoption of a step-up approach with the growing economy.

To effectively manage the condition and overcome limitations and barriers in low and middle-income countries, the plan of action that needs to be implemented includes education and training, financial and psychosocial support, and creating more oncology units.

Novel immunotherapy agents hold promise for improving ALL outcomes by allowing for deeper responses and reducing the usual dose of chemotherapy.

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