Question 1

What are the risk factors for pediatric cancer, the way smoking and alcohol are known risk factors in adults?

Dr. Arun Singh Danewa · Accepted Answer

Only about 1% of pediatric tumors are familial or have an identifiable genetic cause. Most arise from spontaneous mutations that the body's own immune checks fail to catch. There is no equivalent of smoking or alcohol as a modifiable risk factor in children. A few infections are established causes, such as Epstein-Barr virus in Burkitt lymphoma and HHV-8 with HIV in Kaposi sarcoma, and hepatitis B vaccination prevents liver cancer, but for most childhood cancers there is no preventive vaccine.

Question 2

Can you recommend a textbook on pediatric cancers that doctors can follow?

Dr. Arun Singh Danewa · Accepted Answer

There are two textbooks: Nathan and Oski, and Lanzkowsky. I recommend Nathan and Oski as the best one. It comes in two parts, one for hematology and one for solid tumors, and it was our reference during training. Today there are other resources as well, such as the Cochrane Library. For any particular pediatric tumor, I am happy to share my protocols and presentations with any doctor who wants them.

Question 3

Is targeted therapy readily available, and what does it cost?

Dr. Arun Singh Danewa · Accepted Answer

It depends on the disease. In ALL, the two major targeted therapies, inotuzumab and blinatumomab, are both available. Inotuzumab is cheaper because it requires only day-care admission; it is easily available, and support schemes exist, for example a second vial free with the first. Blinatumomab is costlier and is given as a 28-day continuous infusion, with hospital admission for the first few days, although a few centres in India provide it free of cost on humanitarian grounds. For brain tumors, targeted therapies are available, again with patient assistance programmes. For neuroblastoma, dinutuximab is costlier, at around 70 to 80 lakh Indian rupees, though the cost has come down with recent policy changes. These targeted therapies are standard of care and FDA approved; they are available or can be imported. The only constraint is cost: some are affordable and some are expensive.

Question 4

In US dollar terms, what is a rough ballpark range for these targeted therapies, since it is the first question doctors face when counselling families?

Dr. Arun Singh Danewa · Accepted Answer

ALL is the most common cancer, and it mostly requires targeted therapy at relapse: every relapse protocol for B-cell ALL now includes inotuzumab or blinatumomab. One cycle of inotuzumab is given on day 1, day 8 and day 15. Blinatumomab costs around 30 to 40 lakh Indian rupees, which is why we hardly offer it to international patients, whereas we use inotuzumab very commonly. In Hodgkin lymphoma, brentuximab and nivolumab immunotherapy costs around 12,000 to 15,000 US dollars, in the same range as inotuzumab. In lymphoma and leukaemia, these targeted therapies are affordable. Blinatumomab and dinutuximab are very costly, and we use them only rarely, perhaps once a year.

Question 5

Can you briefly touch on the role of stem cell transplant in management?

Dr. Arun Singh Danewa · Accepted Answer

The success and the indication for stem cell transplant differ from disease to disease. In pediatric leukaemia there is no role for upfront bone marrow transplant, only selected indications: failure of morphological remission (more than 10% blasts at the end of the first month of treatment), hypodiploidy (fewer than 44 chromosomes), and relapse, where most patients require a transplant.

For benign conditions, the most common indication on the African continent is sickle cell anemia, a lifelong debilitating disease. Gene therapy is coming up, but it will take time. The earlier the transplant, the better the result: I am happy to transplant below 12 years of age; after 12 I hesitate, because the success rate goes down and complications go up. The indications for transplant in sickle cell disease are recurrent pain crises (two or more a year), any stroke, or acute chest syndrome. Whenever a patient is a candidate, transplant early.

There are three types of bone marrow transplant: a matched sibling donor transplant when a fully matched brother or sister is available; a matched unrelated donor transplant from a registry when there is no full match in the family; and a half-matched (haploidentical) transplant from a mother or father. Outcomes follow the same hierarchy, best with a sibling donor and a little lower with a matched unrelated donor. Haploidentical transplant success is generally around 70 to 80%, varying by disease.

Question 6

Other than cancers, do you offer bone marrow transplant for disorders like sickle cell disease? It is very common, and I have lost fellow doctors and many friends to it in their 20s. Is there a cure?

Accepted Answer

Yes, bone marrow transplant is offered, and it is a cure. As Dr. Danewa highlighted, the earlier it is done the better. There is no strict age cutoff; age correlates with outcome because the longer patients wait, the more damage occurs and comorbidities develop, which lowers the success rate. The earlier the condition is identified, the earlier treatment can be offered and the better the chance of success.

Question 7

How effective is CAR T-cell therapy?

Dr. Arun Singh Danewa · Accepted Answer

In relapsed or refractory leukaemia, where prior treatment options offered only a 5 to 10% chance of success, both Western data and four to five years of follow-up on India's own indigenous CAR T-cell programs are now showing 50 to 60% success.

Question 8

For laymen, where does CAR T-cell therapy sit compared with chemotherapy, immunotherapy and targeted therapy? Is it tailored to the genetic makeup of the tumor?

Dr. Arun Singh Danewa · Accepted Answer

No. CAR T-cell therapy is built around a target on the cancer cell. In ALL, one such target is CD19, and another is CD22: these are surface antigens on the cancer cell against which we train the patient's own T cells to go and fight. Normally the immune system, through our T cells, checks the mutations happening in the body; when that checking mechanism fails, cancer develops. In CAR T-cell therapy we take the cells out, teach them again, and send them back to fight the cancer.

Cancer cells are smart: when we target CD19, they can escape by presenting CD22. To overcome this escape mechanism we now use dual CAR T-cell therapy against CD19 and CD22 together. In solid tumors, anti-GD2 CAR T-cell therapy is coming up for neuroblastoma, and CAR T-cell therapy is coming for brain tumors. At a recent cellular therapy meeting in Bengaluru, around 20 to 25 indigenous CAR T-cell therapies were in the early pipeline, expected over the next three to four years, so costs should fall and efficacy rise with dual CAR T-cell therapy. CAR T-cell therapy is the future, but it is not the holy grail on its own: we are still at 40 to 50% in this setting, a long way to go, but up from nothing.

Live Discussion with Dr. Arun Singh Danewa