SUMMARY:Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides of loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density. 
POEMS (Prevention of Early Menopause Study) is a randomized phase III trial designed to evaluate whether the addition of LHRH (Luteinizing Hormone-Releasing Hormone) analog Goserelin (ZOLADEX®), which suppresses the production of estrogens, to Cyclophosphamide based chemotherapy, would reduce POF in breast cancer patients, when compared to chemotherapy alone. Premenopausal patients less than 50 years of age, with hormone negative (ER/PR negative ), Stage I-IIIA breast cancer, scheduled to receive chemotherapy, were randomly assigned to receive standard Cyclophosphamide based chemotherapy with or without monthly ZOLADEX® . Patients in the ZOLADEX® group received 3.6 mg SQ starting 1 week prior to the first dose of chemotherapy. The primary endpoint was ovarian failure at two years (defined as amenorrhea for the prior 6 months AND post-menopausal FSH level). Other endpoints included pregnancy and survival rates. Of the 218 evaluable patients, 135 premenopausal women were evaluable for the primary end point. POF rates were 22% in the chemotherapy alone group and 8% in the ZOLADEX® group (P=0.03). When the definition of POF was more liberal to include EITHER amenorrhea or elevated FSH but not both, POF rates were 45% in the chemotherapy alone group and 20% in the ZOLADEX® group (P=0.006). Among the 218 evaluable patients, more women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). Secondary outcomes also favored the ZOLADEX® group with a Disease free Survival (DFS) rate of 78% in the chemotherapy alone group compared with 89% in the ZOLADEX® group (P=0.04) and Overall Survival (OS) rate of 82% in the chemotherapy alone group compared with 92% in the ZOLADEX® group (P=0.05). The authors concluded that the addition of ZOLADEX® to chemotherapy improved fertility prospects with a lower incidence of Premature Ovarian Failure and more pregnancies. Further, the improved Disease Free Survival and Overall Survival is an important additional perk and prevention of POF with ZOLADEX® may be a consideration not only in premenopausal patients with hormone receptor positive breast cancer but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Moore HC, Unger JM, Phillips K, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA505)</s
Author: RR
PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma
SUMMARY: Non-Hodgkin Lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. PI3K delta signaling is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. PI3K (PhosphatidylInositol 3-Kinase) is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are only expressed in hematopoietic cells. PI3K delta (the delta isoform of PI3K enzyme) is predominantly expressed in leukocytes and plays an important role in the normal B lymphocyte development as well as signal transduction from B cell receptor as well as receptors for various cytokines and chemokines.
PI3K delta is activated by BCR signaling resulting in the production of a second messenger, Phosphatidylinositol 3,4,5-triphosphate (PIP3) which in turn activates Bruton’s Tyrosine Kinase (BTK) and AKT, a prosurvival kinase. Idelalisib (ZYDELIG®) is a highly selective, small molecule, oral inhibitor of the enzyme Phosphoinositide 3-Kinase delta (PI3K delta) and blocks the delta isoform of PI3K enzyme and its signaling pathway, thus promoting apoptosis. The FDA granted ZYDELIG® accelerated approval in relapsed Follicular B-cell Non-Hodgkin Lymphoma and Small Lymphocytic Lymphoma based on the results of a single-arm, open-label, phase II trial. Patients with indolent Non-Hodgkin Lymphomas (N=125), who were refractory to Rituximab (RITUXAN®) and an alkylating agent or had relapsed within 6 months after receipt of these therapies, received ZYDELIG®, 150 mg PO BID. Treatment was continued until disease progression or unacceptable toxicities developed. The median age was 64 years and enrolled patients had received a median of four prior therapies. The indolent Non-Hodgkin Lymphoma subtypes included Follicular lymphoma (N=72), Small Lymphocytic Lymphoma (N=28), Marginal Zone Lymphoma (N=15), and Lymphoplasmacytic Lymphoma with or without Waldenström's Macroglobulinemia (N=10). The primary end point of this study was Overall Response Rate and secondary end points included the Duration of Response, Progression Free Survival, and Safety. The median follow up was 9.7 months. The Overall Response Rate was 57% with 50% partial responses and 6% complete responses. There was no difference in the Reponse Rates across the various subtypes of Indolent Non-Hodgkin Lymphomas. The median time to response was 1.9 months and the median duration of response was 12.5 months. The median Progression Free Survival was 11 months and the Overall Survival at one year was estimated to be 80%. The most common grade 3 or higher adverse events were diarrhea (13%), neutropenia (27%) and elevations in SGOT and SGPT levels (13%). These toxicities were manageable with dose modifications and dose interruptions. The authors concluded that ZYDELIG® has significant single agent activity, with an acceptable safety profile, in heavily pretreated patients with indolent Non Hodgkin Lymphomas. Gopal AK, Kahl BS, de Vos S, et al. N Engl J Med 2014; 370:1008-1018
KADCYLA® beneficial for patients with HER2-positive Advanced Breast Cancer who had previously received HERCEPTIN® and TYKERB®.
KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an antibody-drug conjugate (ADC) comprised of the antibody HERCEPTIN® (Trastuzumab) and a chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, KADCYLA® not only inhibits the HER2 signaling pathways but also delivers Emtansine, a microtubule inhibitor, directly inside the tumor cells and destroys them. In the TH3RESA trial, treatment with KADCYLA® significantly improved Progression Free Survival compared to physicians choice, for those patients who had previously received HERCEPTIN® and TYKERB® (Lapatinib) and this therefore makes KADCYLA® the treatment of choice, for this patient population.
AVASTIN® (Bevacizumab)
The FDA on August 14, 2014 approved AVASTIN® for the treatment of patients with persistent, recurrent or metastatic Cervical Cancer, in combination with TAXOL® (Paclitaxel) and Cisplatin or TAXOL® and Topotecan (HYCAMTIN®). AVASTIN® is a product of Genentech, Inc.
Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU) the RESPONSE trial
SUMMARY: Polycythemia Vera (P. Vera) is a clonal myeloproliferative neoplasm characterized by isolated Erythrocytosis in a majority of the patients, with the remaining demonstrating Erythrocytosis, Leukocytosis and/or Thrombocytosis along with Erythrocytosis. Patients usually present with this disorder in their sixth decade and are often asymptomatic, with the diagnosis made incidentally on routine laboratory evaluation. About 30% of the patients however, may initially present with a thrombotic episode, whereas a small percentage of patients may present with disease related symptoms such as pruritus and fatigue.
Over activation of the JAK-STAT signal transduction pathway caused by V617F mutation, has been implicated in majority of the patients with P. Vera. 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 P. Vera, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. JAK2 mutations such as JAK2 V617F are seen in approximately 95% of patients with P. Vera. The goals of therapy in P. Vera are to maintain the hematocrit at less than 45% and decrease the risk of thrombosis and bleeding. P. Vera is presently managed with periodic phlebotomies, cytoreductive therapy with oral antimetabolite, Hydroxyurea and antiplatelet agents such as low dose aspirin. However, a significant number of patients on these therapies become intolerant or resistant to these treatments, leading to an increased risk of progression. 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 RESPONSE trial is a phase III prospective randomized study in which patients with P. Vera, who were refractory or intolerant of Hydroxyurea were randomized to receive JAKAFI® 10 mg PO, bid (N=110) or Best Available Therapy (BAT), which consisted of investigator choice of monotherapy or observation only (N=112). Eligible patients were phlebotomy dependent patients with splenomegaly (> 450 cubic cm). Patients receiving BAT were allowed to cross over to JAKAFI® group from week 32 onwards. The primary endpoint of this study (composite primary endpoint) was the proportion of patients whose hematocrit was controlled without phlebotomy and whose spleen volume was reduced by 35% or more from baseline, as assessed by MRI imaging at 32 weeks. Secondary endpoints included durable response, Complete Hematological Remission and safety. The primary analysis was conducted when all patients reached week 48 or discontinued therapy. The proportion of patients in the JAKAFI® group who achieved the composite primary endpoint was 21% compared to 1% in the BAT group (P < 0.0001). Seventy seven percent (77%) of the patients in the JAKAFI® group achieved at least one of the two major components of the composite primary endpoint. Put another way, 60% of the patients in the JAKAFI® arm were able to achieve the target hematocrit level in the absence of phlebotomy, compared to 20% in the BAT group. Reduction in the spleen volume by 35% or more was noted in 38% of the patients in the JAKAFI® group compared to 1% in the BAT group. Complete Hematological Remission defined as continuous hematocrit below 45%, as well as normal white blood cells and platelets counts, was achieved in 24% and 9% of patients in JAKAFI® and BAT group respectively (P=0.003). More patients assigned to JAKAFI® group also demonstrated 50% or more improvement in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) 14-item total symptom score, at week 32 compared to BAT (49% vs 5%). Thromboembolic events occurred in one patient assigned to the JAKAFI® group as compared to six patients in the BAT group. The authors concluded that JAKAFI® may represent a new option for treating high risk patients with Polycythemia Vera, who are refractory or intolerant of Hydroxyurea. Jakafi® is superior to Best Available Therapy (BAT) in controlling hematocrit without phlebotomies as well as Splenic Volume. Further, JAKAFI® is also effective in improving P. Vera associated symptoms. Verstovsek S, Kiladjian J, Griesshammer M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7026)
NCCN Guidelines for Survivorship Expanded to Address Two Common Conditions
SUMMARY: The National Comprehensive Cancer Network (NCCN) has expanded its Survivorship Guidelines to include cancer-associated cognitive impairment and Chemotherapy Induced Peripheral Neuropathy. The later is a component of the Adult Cancer Pain section. Dr. Urba discussed the management of Chemotherapy Induced Peripheral Neuropathy at the NCCN 19th annual conference. Approximately 20%-40% of the patients suffer from Chemotherapy Induced Peripheral Neuropathy, which can result in premature discontinuation of treatment. Further, this adverse event in a significant number of patients can persist indefinitely and can be disabling, thus impacting their activities of daily living.
The following chemotherapeutic agents are associated with varying degrees of peripheral neuropathy – Platinum compounds (Cisplatin, Carboplatin and Oxaliplatin), Taxanes (Paclitaxel, Docetaxel), Immunomodulatory agents (Thalidomide, Lenalidomide), Other Microtubule inhibitors (Vincristine, Ixabepilone) and Proteosome Inhibitors (Bortezomib). It may be necessary to screen and rescreen patients for neuropathic pain, as patients may not be forthcoming with this complaint. Management of Neuropathic pain may include systemic treatment with adjuvant analgesics, topical therapies and psychosocial support. The management of Chemotherapy Induced Peripheral Neuropathy has mostly been extrapolated from validated studies on diabetic neuropathy. The first line treatment for Chemotherapy Induced Neuropathic Pain includes antidepressants and anticonvulsants, which if not effective on their own, can be combined with opioids. TriCyclic Antidepressants (TCA’s) such as Amitriptyline and Nortriptyline (PAMELOR®) can be considered as first line choice for appropriate patients, although its mechanism of action is uncertain and 20% of the patients discontinue therapy because of adverse effects.
Patients may be able to better tolerate these agents if started at a lower dose and dose titrated slowly every three to five days. Peripheral neuropathic pain has been attributed to an unbalanced release of norepinephrine and serotonin from the neurons. Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s), including Venlafaxine (EFFEXOR®) and Duloxetine (CYMBALTA®), are better tolerated and have fewer drug interactions than TCA’s. EFFEXOR® in one study significantly relieved Oxaliplatin induced neuropathic pain in more than two thirds of the patients when compared to placebo and a third of the patients had complete pain relief. There is however limited evidence showing a beneficial role of Selective Serotonin Reuptake Inhibitors (SSRI’s) such as Citalopram (CELEXA®) and Paroxetine (PAXIL®) for neuropathic pain. As a note of caution, SNRI’s such as EFFEXOR® and CYMBALTA®, can interact with Tamoxifen, prescribed to patients with breast cancer, preventing Tamoxifen from converting to its active form. The dose of antidepressants needed to alleviate neuropathic pain is not dependent on antidepressant activity and may be lower than that recommended for treatment of depression. The newer anticonvulsants such as Gabapentin (NEURONTIN®), Pregabalin (LYRICA®) are preferable first line agents for the treatment of neuropathic pain rather than traditional, older agents such as Carbamazepine (TEGRETOL®), Phenytoin (DILANTIN®) and Valproate (DEPAKOTE®), as the newer agents are associated with fewer drug interactions. The newer agents bind to the alpha2-delta subunit of the calcium-sensitive channels, modulating neurotransmitter release. Of the newer agents, NEURONTIN® (Gabapentin) is not protein bound and is excreted unchanged in the urine and therefore has fewer drug interactions. If opioids are a consideration for neuropathic pain relief, the lowest dose is recommended. Topical therapies for neuropathic pain have the advantage of controlling pain without systemic side effects. It therefore can be combined with systemic treatment. Lidocaine 5% patches (LIDODERM®) block neuronal sodium channels whereas Capsaicin cream (ZOSTRIX®) stimulates the C fibers to release and subsequently deplete substance P, there by blocking pain signaling to the brain. Diclofenac gel 1% when applied once a day, concentrates in the dermis and has less gastrointestinal side effects and may be beneficial for neuropathic pain. A combination of Ketamine 1% and Amitriptyline 2% cream applied topically has also been promising in a small study. Patients experiencing refractory pain may benefit with the use of Transcutaneous Electrical Nerve Stimulation (TENS), although referral to the pain clinic may be appropriate. Psychosocial support utilizing a team of specialists and social workers/counsellors, should be an integral part of pain management. Kvale E and Urba SG. National Comprehensive Cancer Network (NCCN) 19th Annual Conference, March 13 – 15, 2014; Hollywood, Florida
A Less Intense Schedule of ZOMETA® for Patients with Metastatic Breast Cancer
Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with Breast Cancer with bone metastases. In a study presented at ASCO 2014 meeting, continuing ZOMETA® (Zoledronic acid) for an additional year at the every 12 week schedule was non-inferior to ZOMETA® given every 4 weeks, among patients who had initially received IV bisphosphonates monthly, for one year or longer. This less frequent dosing of ZOMETA® compared with the standard monthly dosing, may be more convenient for the patients and result in less toxicities without compromising efficacy. More information at www.oncoprescribe.com
Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients PFS1, PFS2, OS endpoints
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases will be diagnosed in 2014 and 11,090 will die of the disease. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation can result in significantly longer Progression Free Survival (PFS) and Overall Survival (OS), compared to those patients who receive therapy for a fixed duration of time. Not all studies however, have shown Overall Survival benefit. It has been hypothesized that Continuous Treatment could result in resistance to therapy which in turn could reduce the duration of subsequent remission after first relapse and negatively impact overall survival.
To address this controversy, the authors conducted a pooled analysis of the outcomes of two randomized phase III trials, designed to compare Continuous Treatment to Fixed Duration Therapy. In trail RVMM209, patients were randomized to either induction with Lenolidomide (REVLIMID®), followed by consolidation and subsequent maintenance with REVLIMID® (Continuous Treatment) or Fixed Duration Therapy which entailed REVLIMID® based induction followed by consolidation but no maintenance therapy. In Trial GIMEMA0305, the randomization was between Bortezomib (VELCADE®) based induction followed by maintenance treatment (Continuous Treatment) and VELCADE® induction, with no maintenance treatment (Fixed Duration Therapy). The trial investigators assessed PFS1 as the time from diagnosis to the occurrence of 1st relapse, PFS2 as time from diagnosis to the occurrence of 2nd relapse and Overall Survival as time from diagnosis to death , incorporating the duration of both 1st and 2nd remission. They then evaluated, both PFS1, PFS2 and OS in newly diagnosed multiple myeloma patients who received Continuous Therapy or Fixed Duration Therapy. In this pooled analysis 452 patients received Continuous Treatment and 461 patients received Fixed Duration Therapy .The median follow up was 52 months. Patients receiving Continuous Treatment had significantly prolonged PFS1 (median 35 months vs 24 months, HR 0.58; P<0.0001), PFS2 (median 63 months vs 47 months, HR 0.69, P=0.0001) and OS (median not reached [NR] vs 70 months, HR 0.70, P=0.0019), when compared with Fixed Dose Therapy. The authors evaluated the PFS and OS from first relapse to second relapse and from first relapse to death respectively, and they noted that the outcomes were similar among patients who received Continuous Treatment or Fixed Dose Therapy following initial diagnosis. The authors concluded that Continuous Treatment significantly improved PFS1, PFS2, and OS and findings from this pooled analysis suggested that the clinical benefit observed during first remission was not negated by a shorter second remission and Continuous Treatment did not induce tumor resistance. Continuous Treatment may be essential, as patients with multiple myeloma will always have some residual disease. It should be noted that certain institutions including the Mayo Clinic cap Continuous/Maintenance treatment at approximately 2 years, due to the lack of randomized comparative data, on the value of prolonged maintenance beyond 2 years. Palumbo A, Gay F, Musto P, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8515)
Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse
SUMMARY:Prostate cancer is the most common cancer in American men, excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, over 230,000 new cases of prostate cancer will be diagnosed in 2014 and close to 30,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence.
The American Urological Association suggested that a PSA of 0.2 ng/mL or higher defines PSA failure or relapse, after Radical Prostatectomy. A PSA rise of 2 ng/ml or more above post Radiation Therapy nadir, is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Prostate cancer patients who had thought that they were cured, consequently can experience considerable mental anguish and anxiety, based on these laboratory findings. Androgen Deprivation Therapy (ADT) is often initiated following PSA only relapse with the intent of delaying disease progression although the role of ADT and optimal timing to start ADT (Immediate vs deferred ADT) in this patient population is unknown. Further, ADT can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, etc., which in turn can have a significant negative impact on an individual’s quality of life. In order to determine the significance of benefit if any, with starting ADT while patients are asymptomatic, the authors analyzed data on more than 14,000 patients included in a prospective registry called CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) and of them studied 2,022 men, who had experienced a PSA only relapse following curative surgery or radiation. These patients had clinical stage T3a,N0M0 or lower stage prostate cancer and experienced PSA only relapse (defined as PSA of 0.2 ng/mL or higher after Radical Prostatectomy or three rising PSA values one month apart following radiation treatment. Patients with symptoms, documented metastatic disease by CT scan or bone scan and ADT in the previous 12 months were excluded. Patients in the” Immediate treatment group” initiated ADT within 3 months of PSA relapse and those in the “Deferred treatment group” initiated ADT, 2 or more years after PSA relapse or when they presented with metastasis, symptoms or had a short PSA doubling time. The median age was 69 years, 34% had a Gleason score >7 and 32% received radiotherapy as primary treatment. The median time from primary treatment to PSA relapse was 27 months. Patients were followed for a median of 52.3 months after PSA relapse. The Five-year survival rate for Patients in the” Immediate treatment group” was 85.1% and for those in the “Deferred treatment group” was 87.2% with no significant difference in the all cause mortality. The 10 year survival was identical in both groups at 71.6%. The authors concluded that there is little or no survival benefit for Immediate ADT initiation compared with Deferred ADT initiation (at clinical progression or at least two years after PSA relapse) among prostate cancer patients with PSA only relapse. Therefore delaying ADT for at least 2 years after PSA relapse, following curative therapy for prostate cancer does not worsen overall survival. The findings from this large observational study will need further validation and a randomized phase III trial is underway to confirm these findings. Garcia-Albeniz X, Chan JM, Paciorek AT, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 5003)
Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia
SUMMARY: Acute Myeloid Leukemia (AML) is generally a disease of the elderly and the average age of a patient at the time of diagnosis is about 66 years. According to the American Cancer Society, approximately 18,860 new cases of AML will be diagnosed in 2014 and 10,460 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy. 
The fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the cell surface (transmembrane) and plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. The most common FLT3 mutation is the FLT3-ITD (Internal Tandem Duplication) mutation caused by a tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased leukemia free and overall survival. These mutations are detected using Polymerase Chain Reaction (PCR) based molecular diagnostic DNA testing. Several therapeutic agents are being developed to target FLT3 mutations. Quizartinib (AC220) is an oral tyrosine kinase inhibitor, which has demonstrated activity in patients with both wild type FLT3 as well as those with FLT3-ITD mutations. In this randomized, open label phase II study, the authors evaluated the efficacy and safety of two different, lower dosages of Quizartinib, in patients 18 years of age or older, with FLT3-ITD positive, relapsed or refractory AML. Seventy six patients (N=76) were randomized to receive either Quizartinib 30 mg/day (Group A) or Quizartinib 60 mg/day (Group B), given orally and continuously, during a 28 day treatment cycle. Treatment was continued until relapse, intolerance or Hematopoietic Stem Cell Transplantation (HSCT). Both groups were well balanced except for age over 60 years (42% Group A, 26% Group B) and the percentage with secondary AML (8% Group A, 18% Group B). The composite Complete Remission (CRc) rate included Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), and Complete Remission with incomplete hematologic recovery (CRi). The CRc rate in both groups A and B was 47% and the Overall Response Rate (CRc + Partial Response (PR)) was 61% in Group A and 71% in Group B. Further, 32% of patiens in Group A and 42% in Group B were able to undergo HSCT, after achieving CRc or PR. The most common treatment related adverse events were diarrhea (18%), febrile neutropenia (16%), and QT prolongation (15%). The QT prolongation rate was significantly less with lower doses of Quizartinib, as was used in this study, compared to what was noted with higher doses of Quizartinib utilized in other trials. The authors concluded that Quizartinib is highly effective in relapsed and refractory AML patients with FLT3-ITD mutations, with an acceptable safety profile. Schiller GJ, Tallman MS, Goldberg SL, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7100)