Myeloproliferative Neoplasms (MPNs) were previously known as Myeloproliferative Disorders (MPDs). They are a group of clonal stem cell disorders that are characterised by an over-production of blood cells, be it red cells, white cells or platelets. The four initial subtypes were described between 1845 and 1934. In 1951, William Dameshek put forth the first classification of these disorders and collectively called them Chronic Myeloproliferative Disorders (CMPD). The four initial subtypes were Polycythaemia Rubra Vera (PRV), Essential Thrombocytaemia (ET), Chronic Myeloid Leukaemia (CML) and Primary Myelofibrosis (PMF). Often, we refer to them as just MPDs. This classification remained until 2001, when a new classification was created. Another revision was made in 2008 (The 2008 WHO classification system for Myeloproliferative neoplasms1). These changes were based on the use of molecular markers in addition to the usual histological and clinical features.
The important changes include changing the term CMPD to MPN. While this may seem a simple matter of terminology, it may have some significance for patients. In the past, patients with CMPD (except CML) cannot make Medisave/Medishield claims or insurance policies because CMPDs were not recognised as cancers. With this new terminology of MPN, these disorders should effectively be classified as cancers, and hence, such patients should be able to make the relevant claims. The other changes are more technical and involved the inclusion of Mast Cell diseases, Chronic Eosinophilic Leukaemia – not otherwise specified and MPN undefined. The use of molecular markers is important in determining the clonal nature of these disorders and their classification.
The Scientific Breakthroughs
Understanding the biology and molecular pathways of these MPNs had been slow and tedious. It started back in 1960, when Chronic Myeloid Leukaemia (CML), one of the subtypes of MPN, was found to be linked to the Philadelphia Chromosome. This chromosomal abnormality ultimately led to the discovery of the disease-causing gene mutation BCR-ABL which causes over-production of white cells via the enzyme tyrosine kinase. Even though it took a good 20 to 30 years for this pathway to be elicited, it is well worth the wait. It is this understanding that led to the discovery of other gene mutations like JAK-2. But it is in treatment that this discovery is such an important game-changer in MPNs. The discovery of the genetic mutations led, in turn, to the discovery of life-saving medications like Tyrosine Kinase Inhibitors and JAK-2 Inhibitors.
In the past, even though they were not recognised as “classical neoplasms”, these MPNs can be deadly. Some subtypes like Chronic Myeloid Leukaemia (CML) and Primary Myelofibrosis (PMF) have short median survival. They transform to acute leukaemia, which usually means a death sentence. In the past, median survival is about three years, and by five years most patients with CML and PMF would have died. The most depressing part about treating these patients in the past was that there were no effective treatment options. You can use hydroxyurea or busulphan to control the excessive blood counts, but once the transformation starts, it is a very predictable but extremely dismal outcome. The only chance of a cure was an Allogeneic Stem Cell Transplant, which itself also had a nasty reputation because of its significant treatment-related mortality. Difficulty in finding a suitable donor also greatly limited this curative option. Effectively diagnosing either CML or PMF is a death sentence.
The Shift in Treatment Management of MPNs
You can imagine the joy haematologists felt with the discovery of this new class of cancer drug, Tyrosine Kinase Inhibitors (TKIs). TKIs radically changed the management plans of patients with CML. From a highly fatal condition that requires an Allogeneic Stem Cell Transplant (which itself, is a potentially fatal treatment option and often not available), TKIs had effectively changed CML into a chronic disorder. It would not be too wrong to say that we can now use Diabetes Mellitus as an example for CML. You just need to keep taking oral medications. Median survival had suddenly improved tremendously. From a median survival of three years, median survival exceeding 10 years is to be expected these days. Within a few years of the introduction of the first TKI – imatinib – Allogeneic Stem Cell Transplant was no longer advocated as a first choice option. It is now offered for resistant cases only. The only problem with these TKIs is the high cost of treatment. This cost is compounded by the fact that TKI therapy is to be continued indefinitely. And with a very long survival period expected, it is a very big burden on many patients.
So it was very interesting when I came across this article, Haemopoietic Stem Cell Transplant in China: Current Status and Prospects, by Huang XJ, et al.2They had reviewed the country’s top 42 stem cell transplant centres and noted that 20% of all patients transplanted in China were for CML. This is in stark contrast to the Centre for International Blood and Marrow Transplant Registry (CIBMTR) data and the US data. The CIBMTR data showed that only 6% of all patients transplanted worldwide was for CML in 2006 while the US transplant data showed only 1% in 2009. While the Chinese author Huang XJ had not offered a reason for this “anomaly”, my feeling is that it had a lot to do with the economics of it. An allogeneic stem cell transplant for CML would be a lot cheaper in China when compared to years of using TKIs for CML. Notwithstanding this affordability problem, TKIs had truly made a great impact into the lives of patients with CML.
It is with great anticipation when another new blockbuster, the JAK-2 Inhibitor, is going to be introduced into clinical use here. Janus Kinase 1/2 mutation (JAK2V617F) was discovered in 2005 and was seen in many patients with ET, PRV, PMF and the undefined MPDs. Already, the initial clinical trials with the first JAK-2 inhibitor3,4 – ruxolitinib – had shown great promise in patients with PMF. It had shown significant improvement in reducing splenic size, disease-related symptoms, anaemia and thrombocytopenia as well as improving overall survival.
In summary, after years of excitement for the other types of haematological malignancies where various new drugs had made big impacts into survivals of patients with acute leukaemias, lymphomas and myelomas, it is timely to have a truly significant breakthrough in the treatment of MPNs. Finally, we truly have medications that had made a significant improvement in survival. Hopefully, these breakthroughs will continue to spur further developments.