First diagnosis of rare cancer in child has ‘important prognostic, therapeutic implications’

Belinda Avalos

Daniel P. McMahon

Chronic neutrophilic leukemia is a rare disease, affecting an estimated 200 individuals aged 65 and older across the world.

The disease has long been characterized by sustained elevation of neutrophil count, splenomegaly and poor prognosis in the older adult population.

However, experts more recently found that not all suspected cases of chronic neutrophilic leukemia (CNL) meet these strict criteria.

In an article published in Blood, experts chronicled the groundbreaking diagnosis of CNL for the first time in a child.

The patient — also the first patient identified with a germline CSF3R T618I mutation — underwent a bone marrow transplant at age 11 and remained free of disease more than 1 year later.

“This case should be of particular interest to both adult and pediatric hematologists, as it defies the generally held belief that CNL is a disease restricted to the elderly, and supports the recommendation that CNL be included in the differential diagnosis of unexplained neutrophilia in children and that mutational analysis of CSF3R be performed,” Belinda Avalos, MD, a physician-scientist and vice chair of hematologic oncology at Levine Cancer Institute at Carolinas HealthCare System, whose lab made the diagnosis, told HemOnc Today.

“The frequent association of mutations in other genes such as ASXL1 and SETBP1 with activating CSF3R mutations in adult patients with CNL and the lack of mutations in other genes in the child with CNL, who also had stable disease over a 11-year time period, provide strong evidence that additional mutations are required for progression of CNL, analogous to the secondary molecular alterations observed in transformation of chronic myeloid leukemia,” Avalos added.

HemOnc Today spoke with Avalos and Daniel P. McMahon, MD, physician in pediatric hematology and oncology at Levine Children’s Hospital in Charlotte, N.C., about this rare cancer, what those in the medical community should look for in terms of signs and symptoms, and what treatment options are available for these patients.

Question: How rare is this cancer?

Avalos: CNL is a rare disease that falls into the category of myeloproliferative neoplasms. There have only been about 200 cases in reported literature. In fact, myeloproliferative neoplasms were not even described until 1951 by William Dameshek, MD, and then CNL was officially recognized by WHO in 2001.

Q: How was the pediatric patient diagnosed?

Avalos: The patient was born with an elevated white blood count of 49,000 — about 3.5 times the normal count, with a predominance of neutrophils. She underwent a bone marrow examination at 9 months and had a hypercellular bone marrow, but really nothing else. There was no increase in blasts and no cytogenetic abnormalities. She remained healthy without leukocyte adhesion defect or chronic infections or inflammation. At age 4 years, she was found to have an enlarged spleen. Her counts were monitored and her white blood count remained elevated between 2.5 times and 3.5 times normal. The patient’s pediatric hematologist, Dr. McMahon, was astute enough to know that there had to be something wrong with her, even though he had worked her up for everything known up until this time. He contacted my laboratory and, in collaboration with him, we decided to examine genomic DNA from her blood cells as well as cells from a cheek swab using next generation sequencing. The entire CSF3R gene was sequenced, and we identified an activating T618I mutation in the CSF3R gene. The mutation was reported for the first time in 2013 and has been associated with CNL. Based upon all of this, we diagnosed the pediatric patient with CNL.

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Q: How is the patient doing now?

McMahon: She underwent an allogeneic hematopoietic stem cell transplant more than 1 year ago. Her brother was a perfect match for transplant; he did not have the CSF3R gene and had a normal white blood count. Although the patient no longer has CNL at this time, she is having some complications with graft-versus-host disease.

Q: What should members of the clinical community look for in terms of signs and symptoms so they can accura tely diagnose this cancer type?

Avalos: Speaking from the standpoint of an adult hematologist, I think that what makes the pediatric case very unusual is that this is the first child diagnosed with CNL. The median age of onset of CNL is 66 years; therefore, adult hematologists are more in tune to thinking about this as a potential diagnosis for an older person with persistent neutrophilia and splenomegaly of unknown etiology, and for whom they have ruled out a diagnosis of CML or another myeloproliferative neoplasm through molecular analyses for BCR-ABL, or mutations in JAK2, MPL or CALR. Clinicians should proceed with mutational analysis of the CSF3R gene. These same molecular studies were all performed in this pediatric patient and no gene mutations were identified. The strong message here is that members of the clinical community should consider doing mutational analysis of the CSF3R gene, whether an individual is a child or an adult, if they present with unexplained neutrophilia, splenomegaly and do not have the other molecular abnormalities described.

McMahon: From the standpoint of a pediatrician, a neutrophil disorder with an abnormally high number of neutrophils in infants is most often accompanied by severe infections; however, this patient did not have an infection. We had tested for this and it was negative. This has never been described in a child and I think the odds of running across another pediatric patient with this is going to be low. However, I do think that pediatric hematologists need to keep in mind that if a child does have unexplained neutrophilia, that there are abnormalities in the CSF3R gene that produce neutrophilia. If dealing with unexplained neutrophilia that has persisted for more than 3 months and an individual has splenomegaly and no significant immaturity in the white blood count, peripheral blood or in the bone marrow, then one should clearly consider performing mutational analysis of the CSF3R gene.

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Q: What are treatment options like for these patients?

Avalos: From the adult standpoint, there is really no standard of care. The drug that has been used most commonly is hydroxyurea, which will help control blood count and shrink the spleen but not lead to cure. Another drug that has been used is alpha interferon. There is an ongoing clinical phase 2 trial examining the efficacy of the Jak inhibitor ruxolitinib (Jakafi, Incyte), in terms of its ability to control counts and symptoms. Finally, allogeneic HSCT is the only curative option, but has rarely been used. To my knowledge, there have been no reports of a patient undergoing a transplant in the modern era of molecular diagnostics where we have definitive diagnosis of CNL. This pediatric patient is the first reported to have undergone an allogeneic HSCT, and has no evidence of disease more than 1 year later.

McMahon: I started treating the pediatric patient with hydroxyurea. I knew she had an HLA-identical sibling and I started treatment as such. She had a very good response, her white blood cell count normalized and her splenomegaly almost completely went away. There is not a lot of data on treatment in children.

Q: What are typical outcomes like?

Avalos: Typically, a patient with CNL is an older patient and the prognosis is very poor, with a median survival less than 2 years. The strong association of CSF3R mutations with CNL enables clinicians for the first time to better ascertain the natural history of CNL. Although HSCT is curative, older patients are often not good candidates for transplant due to other comorbidities. However, reduced intensity conditioning and better supportive care have resulted in acceptable rates of nontransplant mortality in older patients with other hematologic disorders undergoing allogeneic HSCT. Only time will tell for patients with CNL.

Q: Is there anything else that you would like to mention?

Avalos: What makes the pediatric case so unique is that this is the first child ever reported with a germline T6I8I CSF3R mutation and the first child to have CNL. Our findings in this patient, along with the patients in the 2009 study published Plo and colleagues in Journal of Experimental Medicine — in which 12 of 16 members of a three-generation pedigree with congenital neutrophilia were found to have a different activating CSF3R germline mutation, with six of the affected family members being 20 years of age or younger — would support the occurrence of CNL in children as an inherited disorder. Our finding, along with her finding, emphasize the importance of looking at germline tissue to see whether someone has a germline mutation causing CNL. Additionally, our finding points to the importance of considering CNL as a potential diagnosis in a child. It is important that clinicians perform serial molecular studies on any patient with CNL to try to determine the chronology of mutation to help better discern which phase the patient may be in, to maintain information on prognosis and the best drug to use to treat a patient. Our findings have important prognostic and therapeutic implications. – by Jennifer Southall

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Reference s :

Druhan LJ, et al. Blood. 2016;doi:10.1182/blood-2016-07-730606.

Elliott MA, et al. Am J Hem. 2016;doi:10.1002/ajh.24284.

Plo I, et al. J Exper Med. 2009;doi:10.1084/jem.20090693.

For more information:

Belinda Avalos, MD, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: belinda.avalos@carolinashealthcare.org.

Daniel P. McMahon, MD, can be reached at Levine Children’s Hospital, 1000 Blythe Blvd., Charlotte, NC 28203; email: daniel.mcmahon@carolinashealthcare.org.

Disclosure: Avalos and McMahon report no relevant financial disclosures.