Blood Journal
Leading the way in experimental and clinical research in hematology

My Say: Notes from a Hawkish Pediatric Hematologist



Crystal L. Mackall, MD
Chief, Pediatric Oncology Branch
National Cancer Institute
Bethesda, MD


Other Pediatric Hematology My Say's
Dr. David Williams - Perspectives on a Career in Pediatric Hematology/Oncology: Little People, Big Lessons




I come to pediatric hematology from the oncologic perspective. I see pediatric leukemia as an enemy to be eradicated and suggest that a military perspective may be useful in addressing this problem, and the problem of cancer in general.  This is not a new idea—a War on Cancer was declared as part of the National Cancer Act of 1971 by then President Richard Nixon.

Leukemias have always been, and continue to be, the single largest cancer killer of children.  While progress made in the treatment of pediatric acute lymphoblastic leukemia (ALL) has been substantial, more than 2000 children still die annually of this disease in the United States alone (www.seer.cancer.gov).  Outcomes for pediatric acute myelogenous leukemia (AML) have not changed significantly in the last 20 years, with survival rates approximating only 50%.

These clinical realities stand in contrast to an ever-increasing body of knowledge regarding the inner workings of the leukemia cell.  We now know that many AMLs and some ALLs are driven by oncogenic translocations encoding aberrant transcription factors, which initiate and sustain the malignant phenotype through a multitude of downstream mediators. In leukemias lacking obvious genetic abnormalities, next generation sequencing can now routinely identify cryptic oncogenic drivers, thus allowing us to dissect, with astonishing precision, the pathways and networks that pediatric leukemias use to sustain their growth.  Functional genomics using large drug screens are being leveraged across academia and biotech in an attempt to translate understanding of the leukemic cell into clinically effective therapies. Many believe that this painstaking process of systematically dissecting the inner workings of the leukemic cell will ultimately produce a comprehensive illumination of the nature of the malignant state and thus generate a steady flow of effective therapeutic interventions.

For others however, the absence of therapies available to target translocations identified over two decades ago and the increasing complexities illuminated by next generation sequencing raise notes of caution.  The fact that B-ALL cells can apparently use dozens of growth signals to feed their final common pathway raises concern that targeting any one, two or three pathways will be futile in the long run. 

Using the military analogy, I can’t help but wonder how the Joint Chiefs of Staff would approach this enemy we call leukemia.  I imagine that they would spend substantial effort on “intelligence gathering” to identify predominant supply lines and vulnerabilities.  But I also imagine that a large portion of their resources would focus on weaponry, creating tools that can kill the tumor, quickly and irreversibly.  Starving an enemy is hard to do.  It takes time, during which new supply lines can open up or the enemy can move on to new territory.  Most of the targeted agents being developed for pediatric leukemia in particular, and cancer in general, interrupt nutritional and growth pathways, and thus seek to starve the tumor cell.  Very few targeted agents kill the tumor cell outright and even fewer kill the tumor stem cell.  This is why even the most effective targeted therapy developed for cancer, imatinib for Ph+ chronic myelogenous leukemia, does not cure the disease.  Chronic therapy without cure may be adequate for an older patient with leukemia, but it remains an issue of substantial concern to pediatric hematologists treating children with this disease.

I worry that cancer research is overleveraged on dissecting the supply lines of the tumor cell based upon the belief that a complete understanding of all of the potential circuits available the tumor is the necessary first step toward eradication of the enemy.  But once we have the circuitry mapped, the challenges of targeting all potential circuits simultaneously, and for a period long enough to starve the tumor and not the host, remain.

Immunotherapy is an investment in weaponry, since T cells and effectors of antibody mediated cell dependent cytotoxicity kill target cells outright. Cure following bone marrow transplant, where immune mediated effects predominate, demonstrates the ability for immune based therapies to eradicate leukemia stem cells.  Recently, the potency of immunotherapeutic weapons has increased greatly. Bi-specific antibodies and Chimeric Antigen Receptors (CARs) potently kill leukemia in vitro and in vivo and early results in clinical trials have been impressive.  I believe we need to invest more resources toward developing therapies such as CARs, immunotoxins, drug conjugates and bi-specifics that kill tumor cells regardless of the inner circuitry they choose to rely on.

This call for investment is not to underestimate the challenges that need to be overcome if the promise of immunotherapy is to be fully realized.  The potency of killing induced by these emerging classes of therapeutics poses real clinical risk, and as immunotherapeutics become more potent, off-tumor, on-target effects will be increasingly toxic. From the military viewpoint, any expression of the intended target on normal tissue will result in “friendly fire”, which is tolerable for B cells, but less so for other vital tissues.  There also remains the critical issue of logistics, a potential Achilles heel for any military campaign. Great progress was made in childhood ALL over the last several decades by carefully administering the right dose of the right weapons at the right time.  If we consider that cytotoxic chemotherapy represents our ground force and drones represent this new class of potent, targeted immunotherapies, we don’t yet know how to sequence the attacks of the ground forces and the drones and whether one could ever imagine a campaign devoid of ground forces.

Finally, any oncologist knows that focusing cancer therapy on only one target is foolhardy, as the genetic heterogeneity of cancer will almost certainly result in immune escape.  Indeed, CD19-negative B-ALL has already emerged in patients treated with CD19 directed therapies.  Thus, curative regimens will need to simultaneously or sequentially target multiple molecules and multifaceted attacks are overwhelmingly more likely effective in the long run than those directed at a single target.

Despite these challenges, the fact remains that an effective military campaign must involve appropriate levels of investment in weaponry suited to the battle.  I believe a strong case can now be made that increased investment in the emerging arsenal of immune based therapeutics is essential if we are to continue progress against cancer in general, and pediatric leukemias in particular.