ASH 2014 - Myeloproliferative neoplasms, Myelodysplasia, Acute lymphocytic leukemia and Acute Myeloid Leukemia

Myelofibrosis
1. From the mutational perspective there are three driver mutations in myelofibrosis: JAK2, MPL and CALR. Nevertheless, there are about 10% of patients that are triple-negative, with worse prognosis. All three mutations activate the JAK2 pathway and respond to JAK2 inhibitors. But, some patients deemed Low-Risk by clinical criteria can move up to High-Risk based on the mutational pattern, therefore transplantations should be offered sooner to them. Several additional passenger mutations have been discovered that reflect clonal evolution and deal mainly with epigenetic phenomena. 

2. Currently, there are three new research avenues in myelofibrosis: 1. Addition of another agent to the JAK2 inhibitor: JAK2 inhibitors are good at decreasing inflammation and spleen, but they are not good at improving blood counts. There are studies combining JAK2 inhibitors with PI3k inhibitors, Hedgehog inhibitors, HiDAC inhibitors, Antifibrotic agents. 2. Exploring selective JAK1 inhibitor: it appears that JAK1 inhibitor may provide anti-inflammatory effects, but it is less effective on the splenomegaly. 3. A promising anti-Telomerase agent is under study with some patients achieving complete remission. Will have to see the actual results in this meeting.

Polycythemia vera (PV)
Just 3 days ago, Ruxolitinib was approved by the FDA for 2nd-line therapy in PV in patients resistant or intolerant to Hydrea. (The presenter summarizes what the standard of care of PV is: you treat with phlebotomy, aspirin and probably Hydrea the majority of PV patiens. The goal is to keep the hematocrit below 45% in order to decrease the risk of thrombosis. The actual indication for Hydrea is patient older than 60 or a history of thrombosis). About 25% of patients do not tolerate Hydrea, and they don't do well. Ruxolitinib becomes an option for these patients (it is estimated that about 25.000 patients are going to need it in the US alone). In this ASH there will be a presentation on QoL with Ruxoilitinib, showing a marked improvement in several aspects with Ruxolitinib.

Essential thrombocythemia (ET)
1. ET is the most benign of the myeloproliferative neoplasms, with nearly normal life-expectancy. It can be treated with aspirin, Hydrea or Anagrelide. Ruxolitinib is not as good in ET compared to its results in Myelofibrosis and PV. It affords adequate response in 70-80% High-Risk ET patients; but may cause significant anemia. 

2. Pegylated-Interferon (Pegassys) has shown activity in both PV and ET, and appears quite effective in both. In this ASH there is going to be a presentation on the impact of the mutation status and response to pegylated interferon in MPN.

Myelodysplasia (MDS)
1. MDS - Negative results of S117 (Azacytidine vs Azacytidine + Vorinostat vs Azacytidine + Lenalidomide)
Enrolled about 280 patients, no difference in response in the three arms, combination therapy more toxic, more patients came out of the study due to toxicity, some evidence of longer PFS with combination, not powered to detect OS benefit. Does not change practice.

2. Rigosertib not effective in 2nd-Line MDS after hypomethylating agents in a Phase 3 trial
OS increased from 5 to about 8 months, not reaching statistical significance. An oral formulation is still being developed with some encouraging results, but it is not ready for prime-time.

3. New treatment options for Low-Risk (LR) MDS
LR-MDS patients are treated with EPO or Lenalidomide (indicated in del-5q MDS, buy often used "off-label" in other settings). But some patients are refractory to these agents (or have high EPO blood levels predicting a poor response to a pharmacologic EPO formulation).
There are two promising agents in this particular setting, and both share the same mechanism of action as ligand traps to the TGF-Beta receptor superfamily (Sotatercept: an activin type IIA receptor-fusion protein, and ACE-536: a modified activin type IIB receptor-fusion protein). It is known that TGF-Beta mediates anemia and chronic inflammation. Some preliminary results show up to 40% response rate (including transfusion-independence) to Sotatercept, and further results are going to be presented at this ASH with both agents. It is interesting to know that these agents are bone-morphogenetic factors that show promise in osteoporosis, multiple myeloma, thalassemia, and Castleman disease.

Newer agents in Acute Lymphoblastic Leukemia (ALL)
The FDA approved Blinatumumab (CD19-CD3 bi-specific antibody) for refractory and relapsed B-Cell ALL. There are other agents under investigation: a CD-19 conjugated to a toxin, Inotuzumab (CD22 conjugated to ozogamycin), CAR-T-Cells. Inotuzumab also appears very promising and it is now on a Phase III trial.

Acute Myeloid Leukemia (AML)
1. Sorafenib + Anthracycline + Cytarabine in AML: Not quite there.
In the SORAML trial Sorafenib was added to standard induction chemotherapy in AML and was found  to increase event-free survival (3-yr EFS 56% vs 38%, with PFS of 21 vs 9 months, in favor of the Sorafenib arm) and relapse-free survival was also superior in the Sorafenib. But no OS advantage was detected (but the study was underpowered to detect it, with only 276 patients). The speaker points out that Sorafenib is used off-label in relapsed FLT3 mutated patients (sometimes in combination with hypomethylating agents) with very good results. Interestingly, the response to sorafenib in the german trial was not restricted to FLT3 mutation+ AML.

2. DH2 inhibitors are promising in IDH2 mutated AML
Isocytrate dehydrogenase-2 (IDH2) is mutated in about 20% of AML. Anti IDH2 agents are clearly EFFECTIVE in this group of patients achieving significant cytoreduction allowing some highly refractory patients to bridge to allo-transplantation.