Although some of our readers may not be aware of this, at the beginning of 2006 The Hematologist expanded to publish six issues annually. Concomitant with that change, the make-up of The Hematologist has also changed slightly. The Diffusion article series, the mainstay of The Hematologist, will always appear, but other features may appear intermittently. One of these features, the "Ask The Hematologist" series, has been well received by most readers. Thus far, this series has examined a host of hematologic diseases - from the fairly common (at least as hematologic diseases go), to the rare, and even to the "really rare."
Over the next five or more issues, we intend to focus on the "really rare" diseases. In many instances you might not be able to find a review on the subject of these disorders, the available review might be outdated, or you might have a hard time tracking down a particular expert. Therefore, over the next several issues we will try to cover some of these disorders. I welcome your suggestions for diseases to cover or experts who can write about them.
To start things off, I will cover the very rare disorder, juvenile myelomonocytic leukemia (JMML).
The Typical Patient
A 14-month-old boy experienced a normal birth, but lately his parents have noticed a protuberant abdomen and frequent infections. On physical exam he has marked hepatosplenomegaly. Laboratory values show a moderate leukocytosis with an absolute monocytosis, anemia, and thrombocytopenia. His fetal hemoglobin is significantly elevated. A bone marrow exam shows myeloid hyperplasia with minimal dysplastic changes. Karyotype analysis is normal. Culture of the patient's peripheral blood mononuclear cells reveals selective hypersensitivity to GM-CSF.
What is JMML?
Twenty years ago, JMML was an obscure, ill-defined leukemia with a dismal prognosis, and was known by a multitude of different names, including juvenile chronic myelogenous leukemia (JCML). The name JCML was a real misnomer, as this disease has no association whatsoever with the BCR/ABL fusion gene. In the ensuing years, scientists and clinicians have greatly advanced our understanding of JMML so that it is now a well-defined entity with known pathogenesis and internationally-accepted, standard minimal diagnostic criteria. We now know that this myeloid leukemia is an epitomal example of a disorder with definite genetic predispositions related to neurofibromatosis type 1 and Noonan syndrome. Further, the pathogenesis of JMML is intricately linked to perturbed cellular signaling involving the cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the Ras signal transduction pathway. JMML has been one of the diseases to clearly prove that modeling genetic disorders in mice has scientific validity for human pathogenetic mechanisms of disease.
Therapy for JMML
Moderate- to high-dose chemotherapy regimens have proven to have little utility in JMML due to a rapid relapse of the leukemia. Only allogeneic stem cell transplantation has resulted in extended survival. Early relapse still remains the major problem with stem cell transplantation for JMML, but some improvements on this front have been recently noted with the relapse rate dropping to 35 percent in a recent study from the EWOG-MDS/EBMT group. This group took the clinical investigative approach to transplant newly-diagnosed JMML patients as soon as possible following diagnosis. The Children's Oncology Group (COG) took a somewhat different approach in the currently active multi-modality phase II window/phase III protocol (#AAML0122). In this protocol, 13-cis retinoic acid, chemotherapy, and splenectomy are employed in attempts to tumor-debulk the patient as much as possible prior to stem cell transplantation. 13-cis retinoic acid is also employed post-transplant to attempt to reduce the relapse rate. Conditioning regimens prior to transplantation also differ. In addition, the COG built a two-month phase II window into the AAML0122 trial in attempts to study moleculary-targeted, mechanism-based therapeutics in newly-diagnosed JMML patients. While the phase III portion of the COG trial is still accruing patients, preliminary results of the first phase II window therapeutic have been reported. Tipifarnib, a farnesyltransferase inhibitor, has preliminarily shown a 58 percent response rate in JMML. Whether tipifarnib actually represents a targeted therapeutic in JMML is still under investigation. Nevertheless, the results from both the EWOG-MDS/EBMT and the COG demonstrate that clinical advances in JMML are beginning.
Bottom Line
Nearly all cases of JMML occur between birth and six years of age. In the vast majority of cases, therapy does not need to begin immediately, and there is usually time to gather sufficient data and apply the international diagnostic criteria to determine if JMML is the most correct diagnosis. Following a confirmation of a diagnosis of JMML, a search should ensue immediately for a HLA-identical donor. Whether other therapeutic maneuvers are attempted while the transplant process is proceeding is still a matter of experimental investigation.
References
Competing Interests
Dr. Emanuel indicated no relevant conflicts of interest.
