Childhood Leukaemia Treatment: Targeted Therapy and Cost

Childhood leukaemia treatment now cures most children. Acute lymphoblastic leukaemia (ALL) survival has risen to about 90% in Western centres, largely with the same chemotherapy drugs used since 1970, now matched to each leukaemia's genetics. Targeted therapy, CAR T-cell therapy and bone marrow transplant rescue many children who relapse, and their cost varies widely, from affordable to very expensive.

Dr. Arun Singh Danewa, Senior Consultant – Pediatric-Haemato-Oncology & Bone Marrow Transplant (Unit II), Artemis Hospitals, Gurugram, India, treats the full range of childhood leukaemias. This article sets out his account of how ALL, acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML) are treated, where targeted therapy and CAR T-cell therapy fit, when a transplant is needed, and what the newer drugs cost. The complete guide to childhood cancer gives the overview, and the warning signs and diagnosis article covers how leukaemia is detected and classified.

Acute lymphoblastic leukaemia: from 20% to 90% survival

ALL is the most common childhood cancer. Its treatment began in 1948 with a folic acid antagonist, and in the early decades, Dr. Danewa said, only about two in ten children survived. Today eight or nine in ten do.

The surprise is how little the core drugs have changed. The backbone of ALL treatment is four drugs: vincristine, a corticosteroid, L-asparaginase and an anthracycline such as daunorubicin. All four were available in 1970. Dr. Danewa attributes the rise from 30 to 40% survival to around 90% to two things.

1. Understanding the biology. Genetic and chromosomal testing now tells the team which leukaemia needs three drugs and which needs four, which needs more asparaginase or more steroid, and which needs a targeted drug added. Treatment intensity follows the disease rather than a single fixed recipe.
2. Supportive care. Leukaemia and its treatment leave a child with very low immunity. Better antibiotics and infection management mean far fewer children die of complications.

The gap between continents

The 90% figure is Western data. Dr. Danewa estimated that leading Indian centres reach 80 to 85%, and that in parts of Africa survival may be as low as 40 to 50%. His view is that joint work and communication between doctors can close the gap, first to 80 to 85% and in time to 90 to 95%.

Radiotherapy has almost disappeared from ALL treatment

When Dr. Danewa began his paediatric training in 2010, nearly every child with ALL received radiotherapy to the brain. The cost to a developing brain was severe: lower cognitive ability, memory loss and poor school performance. Better drugs and better stratification have changed that. Brain radiotherapy is now reserved for the few children who have leukaemia cells (blasts) in the brain.

Targeted therapy for childhood leukaemia

Targeted therapy works by recognising a marker on the surface of the leukaemia cell. The pathologist reports which markers the leukaemia carries, such as CD19, CD22 or CD20, and drugs are directed at them. The advantage, as Dr. Danewa explained it, is selectivity: chemotherapy kills leukaemia cells and normal cells alike, whereas targeted therapy concentrates its effect on the cancer cells, so side effects are fewer.

When Dr. Danewa started his oncology training, these drugs were new and used only at relapse. Studies now support using them upfront, with very good results. His prediction is that by 2030 the picture will have changed again, with targeted therapy taking over much of the upfront treatment of ALL. In his words, the future is targeted therapy.

A subset known as Philadelphia-like (Ph-like) ALL also has targeted options: JAK inhibitors or tyrosine kinase inhibitors (TKIs), depending on the genetic lesion.

Two targeted drugs dominate relapsed ALL, and every relapse protocol now includes one of them.

• Inotuzumab is an antibody-drug conjugate directed at CD22. It needs only day-care admission. One cycle is given on day 1, day 8 and day 15.
• Blinatumomab is a bispecific antibody that links the patient's T cells to CD19 on the leukaemia cell. It is given as a continuous infusion over 28 days, with the first days in hospital and the rest in hospital or through a portable pump.

CAR T-cell therapy for relapsed childhood leukaemia

CAR T-cell therapy uses the child's own immune system as the treatment. T cells are collected from the patient, engineered in the laboratory to carry a chimeric antigen receptor (CAR) that recognises a target on the cancer cell, and infused back to seek out and kill the leukaemia. The full process, from cell collection to recovery, is set out in Dr. Akash Khandelwal's complete guide to CAR-T cell therapy.

Dr. Danewa explained the logic in terms of immune surveillance. A person's T cells continually check for abnormal cells, and cancer develops when that checking fails. CAR T-cell therapy takes the cells out, teaches them again and sends them back to fight. In ALL the main target is CD19. CD19 is also present on normal B cells, so CAR T-cell therapy directed at CD19 depletes healthy B cells as well, which is why children need monitoring and sometimes antibody replacement afterwards.

How effective it is

In relapsed or refractory leukaemia, where no therapy works, the chance of success used to be 5 to 10%. Dr. Danewa cited long-term Western data showing around 50 to 60% success with CAR T-cell therapy, and early follow-up of India's indigenous CAR T-cell products suggesting similar results. He was clear that it is not a holy grail on its own: there is a long way still to go, but from almost nothing the field now offers a real chance.

Dual targets and what comes next

Cancer cells adapt. Target CD19, and some leukaemias escape by losing it while still presenting CD22. To overcome that escape, dual CAR T-cell therapy directed at CD19 and CD22 together is now in clinical trials. Dr. Danewa described a recent cellular therapy meeting in Bengaluru at which around 20 to 25 indigenous CAR T-cell therapies were reported in the early pipeline for the next three to four years. He expects costs to fall and efficacy to rise as they arrive. CAR T-cell therapy for solid tumours, including anti-GD2 products for neuroblastoma and products for brain tumours, is also in development.

Acute myeloid leukaemia (AML) in children

AML is the second most common leukaemia in children, and treatment results remain a little behind ALL. Long-term survival in childhood AML is around 60 to 70% in well-resourced centres. Dr. Danewa identified three forces moving it forward.

• Supportive care, which has reduced treatment toxicity and non-relapse mortality, meaning deaths caused by complications of treatment rather than by the leukaemia.
• Bone marrow transplant, including half-matched (haploidentical) transplant, now an established option, allowing many children who relapse after initial treatment to be brought under control.
• Genetics. NGS divides AML into favourable and unfavourable groups. Children with favourable genetics do well with chemotherapy alone. Children with unfavourable genetics receive chemotherapy and are assessed on their response: a good response means continuing chemotherapy, while a poor response means a bone marrow transplant at the first opportunity.

AML has fewer targets than ALL, but several are in use:

• Gemtuzumab, an antibody-drug conjugate directed at CD33.
• Venetoclax, now available as a generic, used in refractory AML that does not respond to standard chemotherapy.
• FLT3 inhibitors, tablets for leukaemias carrying an FLT3 mutation, now available in successive generations. They help bring the disease into remission and can be given as maintenance after transplant to prevent relapse.

CAR T-cell therapy is not yet available for AML. AML cells lack a clean target equivalent to CD19 or CD22 in ALL, and they can escape the antigen being targeted. Dr. Danewa expects that science may eventually close that gap.

Chronic myeloid leukaemia (CML) in children

Chronic myeloid leukaemia is rare in children and, in its chronic phase, is controlled with tablets taken as an outpatient. Dr. Danewa likened childhood CML to the Atacama Desert flowering after rain that comes once in five to seven years: a rare event. He sees three or four children with CML a year.

CML was the first cancer to be controlled by a pill designed against its specific molecular abnormality. Imatinib, a tyrosine kinase inhibitor (TKI), was approved in 2001 and made the cover of Time magazine. The excitement about a cure applied to CML alone: the drug targets the abnormality specific to that leukaemia. Second-generation TKIs (dasatinib and nilotinib), the third-generation ponatinib and, most recently, asciminib followed.

Because tablets control the chronic phase, the skill lies in monitoring: regular testing shows whether the response is adequate and when to switch to a second-generation drug.

When a child with leukaemia needs a bone marrow transplant

There is no role for upfront bone marrow transplant in childhood ALL, Dr. Danewa said. Transplant is reserved for selected indications:

1. Failure to achieve remission. More than 10% blasts in the marrow at the end of induction, the first month of treatment, marks failure of morphological remission, the threshold Dr. Danewa gave; many protocols use 5%.
2. Hypodiploidy, meaning fewer than 44 chromosomes in the leukaemia cells.
3. Relapse. Children whose leukaemia returns early, or responds poorly to relapse treatment, generally need a transplant; some late relapses can be cured with chemotherapy and immunotherapy alone.

There are three types of donor, and outcomes follow the same order.

Indicative costs for matched sibling, matched unrelated donor and haploidentical transplants are published separately.

Transplant also cures non-malignant blood disorders. In Africa the most common indication is sickle cell disease, where Dr. Danewa prefers to transplant before age 12 and treats recurrent pain crises (two or more a year), stroke or acute chest syndrome as indications. His separate masterclass on sickle cell disease and bone marrow transplant covers that in depth.

Childhood leukaemia treatment cost: targeted therapy and CAR T-cells

The cost of childhood leukaemia treatment rises mainly when newer drugs are needed: most targeted therapies are affordable in Dr. Danewa's assessment, while blinatumomab and indigenous CAR T-cell therapy each cost 30 to 40 lakh rupees. Asked whether targeted therapy is readily available and what it costs, Dr. Danewa's answer was that the standard-of-care, FDA-approved drugs are available or can be imported. The constraint is cost: some are affordable, some are expensive. The figures he gave are below.

In leukaemia and lymphoma, Dr. Danewa considers these targeted therapies affordable. Blinatumomab and dinutuximab are the exceptions: very costly, and used perhaps once a year in his practice. For brain tumours, targeted drugs are available with patient assistance programmes, as described in the solid tumours article.

The practical consequence for families travelling for treatment is that the expensive phase is usually short. Diagnosis, stratification and the start of treatment happen at the specialist centre; the remaining chemotherapy uses drugs that are available almost everywhere and can be continued at home. Indicative costs for chemotherapy and immunotherapy are published separately. Related blood disorders are covered on the haematology hub. Dr. Danewa's full answers on cost, transplant and CAR T-cell therapy are in the Live Discussion.