Impact of More Restrictive Blood Transfusion Strategies on Clinical Outcomes A Meta-analysis and Systematic Review

SUMMARY: The traditional hemoglobin trigger to recommend blood transfusions for majority of the Health Care Providers is between 7.5 and 9 g/dl. The clinical rationale is based on the premise that increasing Hgb levels increases blood oxygen content and possible oxygen delivery to the tissues. However, there are no randomized trials validating improved oxygen delivery to tissues or better clinical outcomes in any setting at this hemoglobin transfusion trigger. The authors in this provocative study conducted a comprehensive research and performed a Primary and Secondary meta-analysis. In their primary meta-analysis, they reviewed the pooled data from 3 randomized clinical trials with 2364 patients and in these trials, a less than 7g/dl hemoglobin as a transfusion trigger (restrictive transfusion strategy) was compared with a more liberal transfusion strategy and outcomes were evaluated. These endpoints included mortality, acute coronary syndrome, pulmonary edema, infections and re-bleeding risk. The combined data from these 3 trials showed that a restrictive transfusion strategy resulted in a 26% mortality reduction in hospitalized patients, 20% reduction in total mortality, 36% reduction in the risk of re-bleeding, 56% reduction in acute coronary syndrome, 52% reduction in the incidence of pulmonary edema and 14% reduction in bacterial infections, compared with a more liberal transfusion strategy. The secondary meta-analysis evaluated patients in 16 trials (these were excluded from the primary meta-analysis) that used a less restrictive transfusion trigger (hemoglobin transfusion triggers of 7.5-10g/dl) and the authors noted that outcomes were not improved with a more liberal transfusion strategy. Further it was also noted that several observational studies have shown that Hgb levels of 5-6g/dl was well tolerated in normovolemic patients without effecting oxygen delivery. Contrary to clinical presumptions, these counter-intuitive findings can be explained based on sound physiologic principles. Normovolemic hemodilution following administration of crystalloid or colloid solutions, to replace blood loss, has been associated with a reduction in systemic vascular resistance, increase in cardiac output, coronary and cerebral blood flow and synthesis of 2,3-diphosphoglycerate in red blood cells thus maintaining movement of oxygen from red blood cells to body tissues. Liberal blood transfusions may in fact impair oxygen uptake by vital tissues by increasing the blood viscosity and the resulting loss of RBC function during preservation and storage of blood. Studies have also shown that in patients with gastrointestinal bleeding, restrictive transfusion strategy results in a lower portal blood pressure and less recurrent bleeding, as higher blood pressures might disrupt a thrombus plug. The authors following this clinically relevant meta-analysis concluded that restrictive transfusion strategy resulted in better outcomes and transfusion triggers should be evidence based. Salpeter SR, Buckley JS and Chatterjee S. The American Journal of Medicine 2014;127:124-131

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

SUMMARY: Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s tyrosine kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the BCR, Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, NF-κB pathways and resulting B-cell activation and proliferation. IMBRUVICA® (Ibrutinib, PCI-32765) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). The FDA granted accelerated approval of IMBRUVICA® for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) who had received at least one prior therapy. This approval was based on the outcomes in a select group of 48 patients who were a part of a larger group of 85 patients, enrolled in a multicenter single arm phase Ib/II trial. The median age was 67 years and 71% were male. Patients had a median number of 4 prior treatments and had an ECOG PS of 0-1. Patients in this group received IMBRUVICA® 420 mg PO daily until disease progression or unacceptable toxicity. The overall response rate was 58.3% as assessed by an independent review committee. No complete responses were seen and the response duration ranged from 5.6 to over 24 months. This analysis did not include data from those patients enrolled in the trial who received IMBRUVICA® 840 mg PO daily or those with Small Lymphocytic Lymphoma (N=37). The most common toxicities included fatigue, myalgias and arthralgias, cytopenias, nausea, diarrhea, fever and rash. Transient asymptomatic increase in lymphocyte count with resolution of lymphadenopathy and splenomegaly was common but resolved with continued treatment. The confirmatory RESONATE trial is a multicenter, randomized, open-label Phase III study in which single agent IMBRUVICA® was compared to single agent ARZERRA® (Ofatumumab) in patients with relapsed or refractory CLL or Small Lymphocytic Lymphoma . This was a part of the requirement by the FDA. Enrolled patients had measurable nodal disease and were not eligible for treatment with purine analog-based therapy. In this study, 391 patients who had received at least one prior therapy, were enrolled and randomized to receive 420 mg of IMBRUVICA® orally once daily or ARZERRA® given intravenously. Treatment was given over a period of 24 weeks until disease progression or unacceptable toxicity. Patients randomized to the ARZERRA® group on disease progression were allowed to receive treatment with IMBRUVICA®. The primary endpoint of this study was progression-free survival and the secondary endpoint was overall survival. Following recommendations from the Independent Data Monitoring Committee (IDMC), the study was stopped earlier, as the primary endpoint as well as an important secondary endpoint of the study were met. At the planned interim analysis, patients in the IMBRUVICA® group showed a statistically significant improvement in progression-free survival, the primary endpoint of the study as well as a statistically significant improvement in overall survival, the secondary endpoint of the trial. This data confirmed the efficacy of IMBRUVICA® and gives patients with CLL, an important new treatment option. Byrd JC, Furman RR, Coutre SE, et al. N Engl J Med 2013; 369:32-42

IMBRUVICA® (Ibrutinib)

The FDA on February 12, 2014 granted accelerated approval to IMBRUVICA® for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) who have received at least one prior therapy. The FDA initially granted accelerated approval in November, 2013, for the treatment of patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. IMBRUVICA® is an oral capsule and is a product of Pharmacyclics, Inc.

Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG)

SUMMARY: Treatment of metastatic colorectal cancer with a combination of chemotherapy given along with AVASTIN® is well established. However the duration of therapy remains unclear and it is common to give drug holidays to patients. The outcome in patients who are given these drug holidays remains unclear. The CAIRO3 study is a phase III trial in which patients with previously untreated, unresectable metastatic colorectal cancer received induction treatment with six cycles of Capecitabine (XELODA®)/Oxaliplatin (ELOXATIN®) plus Bevacizumab (AVASTIN®) – CAPOX-B. Patients who had not progressed during induction and had reponses or had stable disease (N=558) were then randomized to receive either XELODA® at 625 mg/m2 twice daily along with AVASTIN® at 7.5 mg/kg every 3 weeks or be observed. Upon first progression, patients in both treatment groups were treated with CAPOX-B until second progression and this was considered the primary endpoint for this study. Secondary endpoints included Overall Survival (OS). Median follow up was 40 months. The median time to second progression from randomization was 19.8 months in the maintenance group and 15 months in the observation group (HR=0.63; P<0.001) The time to first progression in the maintenance treatment group was 8.5 months versus 4.1 months in the observation group (HR 0.41; P<0.001). The time to second progression following treatment with CAPOX-B was 11.8 months in the maintenance group versus 10.5 months for the observation group (HR 0.77; P=0.007), representing a 23% reduction in the risk of progression. The adjusted median OS was 21.7 months with maintenance treatment and 18.2 months in the observation group (HR=0.80; P=0.035). Treatment was well tolerated with slight increase in hand-foot syndrome and neurotoxicity in the maintenance group. Based on this data, the authors recommended maintenance treatment with XELODA® and AVASTIN® until progression or unacceptable toxicity, following 6 cycles of efficacious treatment with CAPOX-B. It is important to note that in the SAKK 41/06 trial conducted by the Swiss Group, observation alone was non-inferior to single agent maintenance AVASTIN® following initial chemotherapy, suggesting that the addition of fluoropyrimidine (XELODA®) chemotherapy to AVASTIN® as maintenance treatment, improves time to progression and median OS in patients with metastatic colorectal cancer. Koopman M, Simkens LH, Ten Tije, AJ et al. J Clin Oncol 31, 2013 (suppl; abstr 3502)

Clinical Cancer Advances 2013 Annual Report on Progress Against Cancer From the American Society of Clinical Oncology

SUMMARY: Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoints are an area of increasing interest as they utilize the patient’s immune system to reject cancer cells. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte Activation . The T cells of the immune system play a very important role in modulating the immune system. EFFECTOR T cells include Cytotoxic T cells, Helper T cells, and Natural Killer (NK) cells, that enable the immune system to destroy cancer cells and pathogens. The REGULATORY T cells however, suppress immune response. Under normal circumstances, inhibition of an intense immune response and switching off the EFFECTOR T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. The mechanism can be compared to a lock and key where the appropriate Ligand (KEY) binds to the Immune checkpoint protein/receptor (LOCK) and activates or inhibits a T lymphocyte. With the ongoing understanding of tumor immunology and the recognition of Immune checkpoint proteins, researchers have focused on the development of antibodies that either target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4, PD-1, IDO, etc. (LOCK) or target the inhibitory soluble Ligands or antigens that are located on the surface of certain cancer cells (KEY) that bind to these Immune check point proteins/receptors. By doing so, one would expect to unleash the EFFECTOR T cells resulting in T cell proliferation, activation and a therapeutic response. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA-4, was approved by the FDA in March 2011 and has been shown to prolong overall survival in patients with previously treated unresectable or metastatic melanoma. The next immune check point protein/receptor studied for targeted therapy was PD-1. Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody that demonstrated a 38% rapid and durable response rate and a more than 7 month median progression-free survival in patients with advanced melanoma, regardless of their prior therapy with YERVOY®. Nivolumab, another PD-1 targeted antibody demonstrated remarkable efficacy in a Phase I study with an overall response rate of 30%, median survival of 16.8 months and a 2 year survival of 44%. Based on this provocative data, a combination of Nivolumab and YERVOY® were studied in patients with advanced Stage III or IV melanoma who had received up to three prior therapies.. The idea was to block both the Immune checkpoints, PD-1 and CTLA-4, for improved efficacy. Fifty three (N=53) patients were treated with a combination of these two agents and 33 patients received these agents sequentially. Indeed, the highest response rate was over 50% in the combination group with 30% of these patients experienced a more than 80% response rate at 12 weeks of treatment whereas the response rate in the sequential treatment group was 20%. This preliminary study confirmed that blocking multiple Immune checkpoint proteins/receptors may result in rapid and durable responses in patients with advanced malignant melanoma. Phase III studies are underway to confirm this efficacy data and this concept is also being studied in other tumor types. Targeting/inhibiting the ligands (KEY) and preventing their binding to the Immune checkpoint protein/receptor, is another approach to stimulate antitumor immune response. PD-L1 protein (Ligand) which is often elevated in melanoma tumor cells, bind to PD-1 check point protein/receptor and can inhibit T cells and escape immune surveillance. An investigational PD-L1 targeted (Ligand targeted) engineered antibody (MPDL3280A) demonstrated a rapid response in 26% of the 45 patients with metastatic melanoma and the benefit was more so in those tumors expressing PD-L1. Promising activity has also been seen in advanced renal cell carcinoma. Antibodies targeting the Immune checkpoint receptor/protein or the Ligands binding to these receptors, are being developed, to carry payloads that are lethal to the checkpoint protein/receptor or Ligand. In conclusion, identifying as well as inhibiting certain Immune checkpoint proteins/receptors and/or Ligands that bind to these receptors, may give us new insights in the field of tumor immunology, resulting in better outcome for our cancer patients. Patel JD, Krilov L, Adams S, et al. J Clin Oncol 2013;32:129-160

Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial

SUMMARY: Over 90% of all Thyroid cancers are classified as Differentiated Thyroid Cancers (DTC) with Papillary, Follicular and Hürthle cell histologies. Approximately 5% to 15% of these patients develop resistance to RadioActive Iodine (RAI). NEXAVAR® is a multi-targeted tyrosine kinase inhibitor and prevents cancer growth by inhibiting multiple kinases that are involved in cell proliferation and angiogenesis. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg PO BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). The median duration of partial response was 10.2 months. Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. It should be noted that approximately 70% of patients in the placebo group were allowed to crossover to receive open-label NEXAVAR® and this could impact the OS data. The most common adverse events in the NEXAVAR® group included hand–foot skin reactions, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® nearly doubled the PFS compared to placebo, in this select group of patients with advanced DTC and is the first and only FDA approved therapy for Differentiated Thyroid Cancers. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)

Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial

SUMMARY: Over 90% of all Thyroid cancers are classified as Differentiated Thyroid Cancers (DTC) with Papillary, Follicular and Hürthle cell histologies. Approximately 5% to 15% of these patients develop resistance to RadioActive Iodine (RAI). NEXAVAR® is a multi-targeted tyrosine kinase inhibitor and prevents cancer growth by inhibiting multiple kinases that are involved in cell proliferation and angiogenesis. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg PO BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). The median duration of partial response was 10.2 months. Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. It should be noted that approximately 70% of patients in the placebo group were allowed to crossover to receive open-label NEXAVAR® and this may impact the OS data. The most common adverse events in the NEXAVAR® group included hand–foot skin reactions, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® nearly doubled the PFS compared to placebo, in this select group of patients with advanced DTC and is the first and only FDA approved therapy for Differentiated Thyroid Cancers. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)

Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC) Results of phase III PREVAIL study

SUMMARY: Prostate Cancer is driven by androgens (primarily testosterone) and androgen signaling pathways. There is evidence to suggest that prostate cancer cells continue to depend on androgen receptor (AR) signaling even in an androgen-deprived environment. Therefore, targeting AR and AR signaling pathways remains a rational approach in the treatment of Castration Resistant Prostate Cancer (CRPC). The first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. XTANDI® (Enzalutamide) is a second-generation anti-androgen with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway. XTANDI® was first approved by the FDA in 2012, for the treatment of patients with metastatic CRPC who have previously received TAXOTERE® (Docetaxel) based chemotherapy. The PREVAIL study is a double-blind, placebo-controlled, phase III trial in which 1,717 chemotherapy-naive patients with mCRPC (metastatic Castrate Resistant Prostate Cancer) were randomly assigned 1:1 to receive either XTANDI® 160 mg/day or placebo. Prior treatment with surgery or radiation therapy for their primary tumor, as well as hormonal intervention with a LHRH (Luteinizing Hormone Releasing Hormone) agonist or first-generation anti-androgen was allowed. The two co-primary endpoints were Overall Survival (OS) and radiographic Progression Free Survival (rPFS), as measured by bone scans and CT scans. At the time of preplanned interim analysis, XTANDI® demonstrated a statistically significant benefit over placebo with a 30% reduction in risk of death (OS: HR= 0.70; P< 0.0001) and an 81% reduction in risk of radiographic Progression Free Survival (rPFS: HR 0.19; P< 0.0001). Further, the response rates were meaningful with 20% complete responses and 39% partial responses (59% Response Rate) compared with 5% Response Rate in the placebo group (P<0.0001). XTANDI® also significantly delayed the median time to chemotherapy by 17 months compared with those who took placebo (P<0.0001). Based on the results of this interim analysis, the Independent Data Monitoring Committee recommended stopping the study and allowing patients in the placebo group to receive XTANDI®. XTANDI® was well tolerated and the most common side effects were hot flashes, weight gain, fatigue, constipation, back and joint pain. The authors concluded that XTANDI® significantly improves OS and rPFS in patients with chemotherapy-naive mCRPC and can significantly delay the need for chemotherapeutic intervention. Beer TM, Armstrong AJ, Sternberg CN, et al. J Clin Oncol 32, 2014 (suppl 4; abstr LBA1)

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II) an international, double-blind, randomised placebo-controlled trial

SUMMARY: NOLVADEX® (Tamoxifen) is a Selective Estrogen Receptor Modulator (SERM), approved by the FDA to also reduce the incidence of breast cancer in women considered to be at high risk (ChemoPrevention). This agent however has been linked to endometrial cancer and thromboembolic phenomenon in some women. ARIMIDEX® is a non-steroidal Aromatase Inhibitor proven to be more efficacious than NOLVADEX® both in metastatic and adjuvant settings. Similar to NOLVADEX®, ARIMIDEX® also prevents the occurrence of new primary tumors in the contralateral breast, in postmenopausal females. With this background, the International Breast Cancer Intervention Study (IBIS) -II trial enrolled 3864 postmenopausal women considered to be at increased risk of breast cancer and randomized them to receive either ARIMIDEX® (Anastrazole) 1 mg QD (N=1920) or Placebo QD (N=1944)for 5 years. Patients were considered to be at high risk if they had a family history of breast cancer, atypical ductal hyperplasia, lobular carcinoma in-situ or dense breast tissue. The median age was 59 years. The primary end point was histologically confirmed Invasive breast cancer or Ductal Carcinoma In- Situ. At a median follow up of 5 years, the incidence of breast cancer in the ARIMIDEX® group was 2% and in the placebo group was 4%. The predicted cumulative incidence of breast cancer after 7 years was 2.8% in the ARIMIDEX® group and 5.6% in the placebo group (HR=0.47; P<0.0001). This represented a 53% reduction in the risk of breast cancer. The adverse events were comparable in both groups with slight increase in the musculoskeletal and vasomotor events noted in the ARIMIDEX® group. The authors concluded that ARIMIDEX® reduced the risk of primary breast cancer by more than 50% in high risk postmenopausal women. Other unrelated studies have shown that acceptance of breast cancer prevention with medications (ChemoPrevention) appeared to be related to education and income, putting emphasis on education and adequate counseling of women, considered to be at high risk. Cuzick J, Sestak I, Forbes JF, et al. The Lancet, Early Online Publication, 12 December 2013

Ruxolitinib for Myelofibrosis – An Update of Its Clinical Effects

SUMMARY: MyeloFibrosis (MF) is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling. JAKAFI® is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. The FDA approval of JAKAFI® for the treatment of Intermediate and high risk Myelofibrosis was based on 2 phase III trials – COMFORT (Controlled Myelofibrosis Study with Oral JAK1/JAK2 Inhibitor Treatment) – I and COMFORT-II studies. In COMFORT-I study, 309 intermediate or high risk patients were randomized to receive either JAKAFI® (N=155) or Placebo (N=154). The primary end point of a 35% or more reduction in spleen size at 24 weeks was noted in 42% of those who received JAKAFI® vs 0.7% in the placebo group (P<0.0001). Most patients in the JAKAFI® group had some reduction in the spleen volume whereas majority of those in the placebo arm had increase in splenomegaly. There was a 46% reduction in the TSS (Total Symptom Score) at week 24 in the JAKAFI® group compared to 5% in the placebo group and majority of patients in the later group had worsening of symptoms (P<0.0001). When JAKAFI® was compared to Best Available Therapy (BAT) in the COMFORT-II study, 28% of the patients in the JAKAFI® group met the primary endpoint of a 35% or more reduction in the spleen volume at 48 weeks compared to none in the BAT group (P<0.0001). Over 55% had a mean decrease in spleen size in the JAKAFI® compared to a 4% mean increase in the BAT group. The 2 year follow up analyses from both these trials showed improved overall survival and a reduction in the risk of death for patients randomized to JAKAFI®, compared to those in the control groups. There was weight gain with alleviation of cachexia and improvements in splenomegaly and symptoms were durable. This benefit was seen in patients regardless of JAK mutations. It remains to be seen if JAKAFI® will benefit patients with Polycythemia Vera and Essential Thrombocythemia. Kantarjian HM, Silver RT, Komrokji RS, et al. Clinical Lymphoma Myeloma and Leukemia 2013; 13:638-645