On December 6, 2015 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, reported data from the completed dose escalation and ongoing expansion stages of the Phase 1 trial of CUDC-907, an oral dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes (Press release, Curis, DEC 6, 2015, View Source [SID:1234508438]). These data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL. The data demonstrated that treatment with CUDC-907 resulted in complete (CRs) and partial responses (PRs) in heavily pretreated patients with relapsed/ refractory diffuse large B cell lymphoma (RR-DLBCL), including those harboring alterations of the MYC oncogene, a poor performing sub-group for which there are no approved targeted therapies.

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In the ongoing Phase 1 trial of CUDC-907, 8 objective responses (3 CRs and 5 PRs) were reported in 18 response-evaluable patients out of a total of 25 patients with RR-DLBCL enrolled in the trial. These results include 1 CR among 2 response-evaluable patients out of a total of 3 patients treated with CUDC-907 in combination with the standard dose of rituximab. The remaining 16 evaluable patients were treated with CUDC-907 monotherapy. In a retrospective post hoc analysis, among the 8 patients who achieved objective responses, 5 had tumors with MYC oncogene alterations (defined as chromosome translocation involving MYC gene locus, gain in MYC gene copy number, or MYC protein over-expression in =40% tumor cells). Among the remaining 3 patients who achieved objective responses, 2 had MYC protein expression in less than 40% of tumor cells, and the third patient’s MYC status is unknown.

In preclinical studies, CUDC-907 treatment of DLBCL cell lines was shown to result in complete suppression of MYC protein levels in a rapid and dose dependent manner. Additionally, anti-tumor activity was observed in multiple in vivo MYC-altered DLBCL models.

"Preliminary data for CUDC-907 in patients with multiply relapsed DLBCL appear encouraging, even in those with MYC-altered lymphoma, providing the rationale for further investigation in a Phase 2 trial," said Dr. Anas Younes, MD, Chief of the Lymphoma Service of the Memorial Sloan Kettering Cancer Center in New York City and the Principal Investigator of the Phase 1 trial. "There is a high unmet need for novel therapies for patients with RR-DLBCL, and particularly for the subset of patients with MYC-altered DLBCL due to their poor prognosis."

Based on promising clinical activity observed in patients with RR-DLBCL, particularly those with cancers harboring MYC alterations, Curis expects to initiate a Phase 2 trial to examine CUDC-907 in patients with MYC-altered DLBCL. In this trial, approximately 120 patients with relapsed/refractory disease will be randomly assigned to receive CUDC-907 as monotherapy or CUDC-907 with the standard dose of rituximab. Patients will remain on treatment until progression of disease, discontinuation for safety reasons, or other reasons for treatment discontinuation. The primary endpoint of the trial is objective response rate with secondary endpoints that include progression free survival, overall survival and duration of response. Positive results with CUDC-907 monotherapy will lead to an expansion of patient enrollment and discussion with the FDA regarding potential registration strategy in this patient population. The rituximab combination treatment arm of the Phase 2 trial is intended to inform the design of a confirmatory, randomized trial of CUDC-907 in combination with rituximab as compared to rituximab in combination with standard of care chemotherapy.

"We are pleased to report promising clinical activity of CUDC-907 in patients with DLBCL, particularly those with tumors that harbor MYC alterations," said Ali Fattaey, Ph.D., Curis’ President and Chief Executive Officer. "These clinical results are consistent with our preclinical observations where CUDC-907 has a rapid and dramatic effect on MYC protein levels and provides significant anti-tumor activity in in vivo models. We are thankful to our patients for their participation in the Phase 1 clinical trial and, based on these data, we expect the start of a Phase 2 trial that will exclusively enroll patients with relapsed/ refractory DLBCL known to have MYC alterations based on pre-specified selection criteria."

The Phase 1 dose escalation and expansion trial was designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose and preliminary anti-cancer activity of oral CUDC-907 in patients with relapsed/refractory lymphoma or multiple myeloma (MM). At the time of data cut-off for the ASH (Free ASH Whitepaper) presentation, a total of 72 patients had been enrolled in the trial, including 25 with RR-DLBCL. In the completed dose escalation phase, patients received CUDC-907 daily (QD, doses: 30 or 60 mg), or intermittently on twice weekly (BIW) or thrice weekly (TIW) schedules (doses: 60, 90, 120 or 150 mg) or on a 5 days on, 2 days off (5/2) schedule (dose: 60 mg). CUDC-907 dosed at 60 mg on the 5/2 schedule was determined to be the recommended Phase 2 dose (RP2D). The expansion phase of the trial is ongoing to assess the safety and tolerability of CUDC-907 at the RP2D of 60 mg 5/2 with or without the standard dose of rituximab.

The most common drug related adverse events (AEs) reported in the study have been low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) have consisted of diarrhea and hyperglycemia, and occurred on the QD, BIW and TIW schedules. No DLT occurred at the RP2D of 60 mg 5/2. Other drug-related Grade 3 or 4 AEs reported in 3 or more patients included thrombocytopenia and neutrophil decrease (hematologic AEs) as well as diarrhea, hyperglycemia and fatigue (non-hematologic AEs).

Out of the 25 patients with RR-DLBCL included in the ASH (Free ASH Whitepaper) presentation, 18 were evaluable for response assessment per protocol at the time of data cut-off. The best responses observed in patients with RR-DLBCL were CR (3 patients), PR (5 patients) stable disease or SD (4 patients) and progressive disease or PD (6 patients). A post hoc analysis of pathology reports and/or tumor samples collected showed that 5 of the 8 patients with objective responses had tumors with alterations in MYC oncogene. MYC alterations in the tumor tissue were determined by established criteria used to identify either MYC gene aberrations (copy number gains or translocations) by fluorescent in situ hybridization (FISH) or MYC protein expression by immunohistochemistry (IHC).

About CUDC-907:

CUDC-907 is an oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoforms. CUDC-907 is currently undergoing investigation in a Phase 1 trial to assess its safety, pharmacokinetics and preliminary anti-cancer activity in patients with relapsed/refractory lymphomas and multiple myeloma. CUDC-907 is also being investigated in a separate Phase 1 trial in patients with advanced solid tumors including those with hormone receptor positive breast cancer or with NUT midline carcinoma. The development of CUDC-907 has been supported in part by The Leukemia & Lymphoma Society (LLS) under a funding agreement established in 2011 between Curis and LLS’s Therapy Acceleration Program. For additional details of CUDC-907’s Phase 1 studies, please refer to www.clinicaltrials.gov (study identifiers: NCT01742988 and NCT02307240).

On December 6, 2015 Takeda Pharmaceutical Company Limited (TSE: 4502) reported post-treatment follow up data from the pivotal phase 2 study of single-agent brentuximab vedotin for the treatment of relapsed or refractory Hodgkin lymphoma following autologous stem cell transplantation (ASCT) (Press release, Takeda, DEC 6, 2015, View Source [SID:1234508435]). The data demonstrated that the estimated five-year overall survival (OS) rate among ADCETRIS-treated patients was 41 percent (95% CI: 31%, 51%); median OS was 40.5 months (95% CI: 28.7, 61.9 [range 1.8 to 72.9+]) and median progression-free survival (PFS) was 9.3 months (95% CI: 7.1 to 12.2 months). The safety profile of ADCETRIS was generally consistent with the existing prescribing information.These results were presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in Orlando, FL.

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"The five year overall survival rates reported in this pivotal trial are very promising in improving the long-term outlook for patients in this setting as outcomes have historically been very poor," said Professor Andreas Engert, M.D., University Hospital of Cologne, Germany. "These data further reinforce the emergence of ADCETRIS as a standard of care for patients with Hodgkin lymphoma who experience relapse or disease progression following salvage therapy and ASCT."

Also presented today at the ASH (Free ASH Whitepaper) annual meeting, data from the phase 3 AETHERA trial of brentuximab vedotin consolidation therapy in Hodgkin lymphoma patients at high risk of relapse following ACST demonstrated that after three years of follow-up, patients treated with brentuximab vedotin continued to show a significant improvement in PFS per investigator assessment (61%; 95% CI:53%, 68% HR 0.52) compared to placebo (43%; 95% CI:36%, 51% HR 0.52). The safety profile of ADCETRIS was generally consistent with the existing prescribing information.

ADCETRIS (brentuximab vedotin) is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. ADCETRIS is currently approved in more than 55 countries for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL). The utility of ADCETRIS is currently being explored across a number of types of cancer, and data from six studies in the ADCETRIS clinical trial program were presented at the ASH (Free ASH Whitepaper) meeting, including four as oral presentations.

"With more than 45 clinical trials across multiple lines of therapy underway and ongoing research focused on understanding the underlying pathogenesis of Hodgkin lymphoma, our commitment to advancing the care of people battling this disease is far-reaching," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

"The positive long-term results from these two pivotal studies are very important in our work to advance the care of people living with Hodgkin lymphoma whose disease has progressed."

About the Studies

Study 1: Five-year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma [Abstract 2736, presented December 6, 2015]
Five-year follow up data from the pivotal phase 2 study evaluating the safety and efficacy of brentuximab vedotin in heavily pre-treated patients with relapsed/refractory Hodgkin lymphoma post-ASCT were presented as a poster by Robert Chen, M.D., City of Hope National Medical Center, California. In the study, the 102 enrolled patients received 1.8 mg/kg brentuximab vedotin once every three weeks as a 30 minute outpatient intravenous (IV) infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints included complete response (CR) rate, duration of response, PFS, OS, safety and tolerability. Survival and disease status were assessed every three months for two years and then every six months through year five. A study protocol amendment removed the requirement of routine CT scanning during follow up, and so disease status was assessed by the investigator. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months.

Patients received a median of nine cycles (range, 1-16) of brentuximab vedotin. The study met its primary endpoint demonstrating 72 percent ORR and a CR rate of 33 percent. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Grade 3 or higher adverse events occurred in ≥5 percent of patients and included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.

Fifteen of the 102 enrolled patients remained in follow-up and in remission at study closure. Of the 15 patients, six received consolidative allogeneic SCT and nine received no further therapy since completing treatment with brentuximab vedotin.
Study 2: Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin After Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse [Abstract 3172, presented December 6, 2015]
Updated efficacy and safety data from the phase 3 AETHERA trial were presented as a poster by John Sweetenham, M.D., Huntsman Cancer Institute, University of Utah. The AETHERA trial was designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with Hodgkin lymphoma with at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included OS, safety and tolerability. Eligible patients must have had a history of refractory Hodgkin lymphoma, have relapsed within one year from receiving frontline chemotherapy and/or had extranodule disease at the time of pre-ASCT relapse. These factors are consistently reported to be associated with poor prognosis after transplant. Patients received brentuximab vedotin or placebo every three weeks for up to approximately one year. This international multi-center trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.

A total of 329 Hodgkin lymphoma patients at risk of relapse were enrolled, including 165 on the brentuximab vedotin arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms.

As reported at the ASH (Free ASH Whitepaper) annual meeting in 2014, the AETHERA trial met its primary endpoint, demonstrating significant improvement in PFS among patients who received brentuximab vedotin compared to patients who received placebo (median of 43 months versus 24 months, respectively; HR=0.57; p=0.001). Approximately three years after the last patient was randomized, consolidation therapy with ADCETRIS continued to show an improvement in PFS. At three years, PFS was 61 percent (95% CI:53–68) for patients in the brentuximab vedotin arm compared to 43 percent (95% CI 36-51) for the placebo arm.

At three years, treatment-emergent peripheral neuropathy resolved for most patients, and no additional secondary malignancies were observed in either treatment arm.

Among the 112 patients in the brentuximab vedotin arm who experienced treatment-emergent peripheral neuropathy, 99 patients (88%) experienced some improvement (23%) or complete resolution (65%) of neuropathy symptoms at the time of analysis.

Secondary malignancies were comparable between the two treatment arms (n=4 brentuximab vedotin, n=2 placebo).
Discontinuation of treatment due to an adverse event (AE) occurred in 54 patients (33%) who received ADCETRIS, most commonly due to peripheral sensory and motor neuropathies (14% and 7%, respectively). Patients who discontinued brentuximab vedotin treatment as a result of an AE received a median of 9.5 cycles (range, 1 to 15). The two-year PFS rate in these patients was 69 percent (95% CI 54–79) versus 82 percent (95% CI 71–89) for patients who completed all 16 treatment cycles.

Six PFS events (2 progressions and 4 deaths) were recorded after the 24-month evaluation period in the brentuximab vedotin arm versus three in the placebo arm (2 progressions and 1 death). The hazard ratio (HR) for PFS per independent review was 0.57 (95% CI 0.41–0.82).

About ADCETRIS

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, one in frontline classical Hodgkin lymphoma and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS Global Important Safety Information
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory (r/r) CD30+ Hodgkin lymphoma (HL):

Following autologous stem cell transplant or
Following at least 2 prior therapies when autologous stem cell transplantation is not a treatment option
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

ADCETRIS is contraindicated for patients who are hypersensitive to ADCETRIS. In addition, combined use of bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.

ADCETRIS can cause serious side effects, including:

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death has been reported in patients treated with ADCETRIS. Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML.

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain.

Pulmonary Toxicity: Cases of pulmonary toxicity have been reported in patients receiving ADCETRIS. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions: Immediate and delayed infusion-related reactions, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS and should be monitored closely and managed according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice.

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): SJS and TEN have been reported. Fatal outcomes have been reported.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored.

Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Population pharmacokinetic analysis indicated that MMAE clearance might be affected by moderate and severe renal impairment, and by low serum albumin concentrations. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.

Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Serious adverse drug reactions were: neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

ADCETRIS was studied as monotherapy in 160 patients in two Phase 2 studies. Across both studies, adverse reactions defined as very common (≥1/10) were: infections, neutropenia, peripheral sensory neuropathy, diarrhea, nausea, vomiting, alopecia, pruritis, myalgia, fatigue, pyrexia, and infusion-related reactions. Adverse reactions defined as common (≥1/100 to <1/10) were: upper respiratory tract infection, herpes zoster, pneumonia, anemia, thrombocytopenia, hyperglycemia, peripheral motor neuropathy, dizziness, demyelinating polyneuropathy, cough, dyspnea, constipation, rash, arthralgia, back pain, and chills.

These are not all of the possible side effects with ADCETRIS. Please refer to Summary of Product Characteristics (SmPC) before prescribing.

On December 6, 2015 Takeda Pharmaceutical Company Limited (TSE: 4502) reported results from the TOURMALINE-MM1 trial presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper), showing that treatment with NINLARO (ixazomib) capsules is effective in extending progression free survival (PFS) with a manageable tolerability profile in patients with relapsed and/or refractory multiple myeloma (Press release, Takeda, DEC 6, 2015, View Source [SID:1234508434]). The TOURMALINE-MM1 trial is an international, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate once-weekly oral ixazomib plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone.

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NINLARO was recently approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The approval was based on the Phase 3 TOURMALINE-MM1 data, which were highlighted at today’s ASH (Free ASH Whitepaper) press briefing. Ixazomib data will be featured in 18 presentations at this year’s ASH (Free ASH Whitepaper) meeting, including an oral presentation on Phase 2 data from an investigational study evaluating the all-oral combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in newly diagnosed multiple myeloma patients.

"The data presented at ASH (Free ASH Whitepaper) this year are the first major output from the comprehensive ixazomib clinical trial program, TOURMALINE, demonstrating Takeda’s ongoing commitment to providing effective and convenient treatment options for patients with multiple myeloma," said Andy Plump, M.D., Ph.D, Takeda Chief Medical and Scientific Officer. "The breadth and depth of the TOURMALINE program allows us to gather important data across a broad range of patients that live with multiple myeloma and to expand on the efficacy and safety profile of our oral proteasome inhibitor, ixazomib. We will continue this and other important clinical trials and look forward to sharing results over the next few years."

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of five pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis.

Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (Abstract #727)

TOURMALINE-MM1 (n= 722) is the first double-blind, placebo-controlled trial with a proteasome inhibitor and has met the primary endpoint at the first interim analysis. Trial results demonstrate a statistically significant (35%) improvement in PFS, with patients treated in the ixazomib arm living for a significantly longer time without their disease worsening compared to patients in the control arm (20.6 months vs. 14.7 months in control group; Hazard Ratio [HR] 0.742; p = 0.012). Overall response rate (ORR) was 78.3% in the ixazomib arm and median duration of response was 20.5 months, vs. 71.5% and 15 months in the control group. Median PFS in high-risk patients (HR 0.543; HR 0.596 in patients with del(17p)) was similar to that in the overall patient population and in standard-risk patients. Adverse events observed with IRd were consistent with reported safety profiles for the individual agents. The most common gr ≥3 adverse events included neutropenia, anemia, thrombocytopenia, and pneumonia. Gastrointestinal events included diarrhea, nausea, and vomiting. Peripheral neuropathy (PN) rates were 28% in the IRd arm vs. 21% in the control arm, 35% vs. 21% had rash events, 8% vs. 10% had acute renal failure, and 4% vs. 3% had heart failure.

"The TOURMALINE-MM1 trial evaluated ixazomib plus lenalidomide and dexamethasone in some of the most common patient types in the relapsed/refractory multiple myeloma setting who are in urgent need of new treatment options due to the complex nature of this disease. This trial enabled us to gather efficacy and safety data across a large variety of patients such as older patients, patients with moderate renal impairment, light chain disease, and high risk cytogenetics," said lead investigator and presenter Philippe Moreau, M.D., University of Nantes, France."

The TOURMALINE-MM1 trial is currently ongoing. Patients continue to be treated to progression in this trial and will be evaluated for long-term outcomes.

Takeda has submitted additional review applications for ixazomib to regulatory authorities around the world, including the European Medicines Agency (EMA), based on the TOURMALINE-MM1 data.

Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (Abstract #26)

Takeda also presented preliminary data from an open-label, multicenter, Phase 2 study that investigates the all-oral triplet combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) as a first line therapy for patients not eligible for transplant. Preliminary data demonstrated comparable activity across treatment arms with a manageable toxicity profile in line with previous ixazomib studies and with manageable myelosuppression. This is the first study to assess ICd for the frontline treatment of multiple myeloma.

The Phase 2 study (n = 70) randomized patients receiving ixazomib, low-dose dexamethasone and two different doses of cyclophosphamide 300 mg/m2 (ICd-300, n = 36) or 400 mg/m2 (ICd-400, n = 34), with a mean duration follow-up of 7.0 months in both arms. Preliminary results across treatment arms demonstrated best unconfirmed complete response plus very good partial response (CR+VGPR) of 27% (ICd-300) and 23% (ICd-400), as well as early overall response rates (ORR) of 80% (ICd-300) and 73% (ICd-400). Toxicity was manageable in both the ICd-300 and ICd-400 arms, but toxicity rates appeared higher with ICd-400. Thrombocytopenia events occurred in 5 patients (no gr ≥3) in the ICd-300 arm and 4 patients (3 gr ≥3) in the ICd-400 arm. Most common adverse events (>15% all patients) included anemia, neutropenia, nausea, PN, diarrhea, vomiting, constipation, and fatigue. Most common gr ≥3 adverse events were neutropenia, anemia and pneumonia; no Grade 3 PN was observed.

"Research has shown that the combination of a proteasome inhibitor with cyclophosphamide and dexamethasone is active in patients with multiple myeloma. As treatment practices for multiple myeloma can vary across regions, it is important that we gain an understanding of the utility of ixazomib in a number of combination settings," said lead investigator and presenter Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens, School of Medicine. "Preliminary data suggest that this may be a viable all-oral triplet regimen. We are committed to gathering additional data of ixazomib in this investigational setting."

About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is the first and only oral proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is administered orally, once-weekly on days 1, 8, and 15 of a 28-day treatment cycle. NINLARO is currently under review by the European Medicines Agency (EMA) and was granted an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP). NINLARO also received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The TOURMALINE clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. Five global Phase 3 trials are ongoing:

· TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

· TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

· TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)

· TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT

· TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis

In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

For additional information on the ongoing Phase 3 studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).

Important Safety Information

WARNINGS AND PRECAUTIONS
· Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.

· Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Adjust dosing for severe symptoms.
· Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

· Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing as needed.

· Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Manage rash with supportive care or with dose modification.

· Hepatotoxicity has been reported with NINLARO. Monitor hepatic enzymes regularly during treatment and adjust dosing as needed

· Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.

ADVERSE REACTIONS
The most common adverse reactions occurring in greater than or equal to 20% of patients treated with NINLARO were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting and back pain.

SPECIAL POPULATIONS
· Hepatic Impairment: Reduce the NINLARO starting dose to 3mg in patients with moderate or severe hepatic impairment
· Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
· Lactation: Advise women to discontinue nursing while on NINLARO.

DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.

INDICATION
NINLARO (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Please see the accompanying full Prescribing Information for NINLARO.

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of plasma cells, or myeloma cells, becomes cancerous and multiplies, increasing the number of plasma cells to a higher than normal level. Because plasma cells circulate widely in the body, they have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with more than 26,000 new cases in the U.S. and 114,000 new cases globally per year.

On December 6, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the presentation of results from a Washington University-sponsored Phase 1 trial of vosaroxin plus azacitidine in patients with myelodysplastic syndrome, and from an analysis of the Company’s Phase 3 VALOR trial of vosaroxin and cytarabine in relapsed/refractory acute myeloid leukemia (AML) at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, Sunesis, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120408 [SID:1234508433]). The posters, titled "A Phase I Study of Vosaroxin plus Azacitidine for Patients with Myelodysplastic Syndrome" (publication number 1686) and "Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo plus Cytarabine in the Phase 3 VALOR Study" (publication number 2560) are available at www.sunesis.com.

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A Phase I Study of Vosaroxin Plus Azacitidine for Patients with Myelodysplastic Syndrome

In a Phase 1/2, open label, dose-escalation trial sponsored by the Washington University School of Medicine, patients with MDS who may have received up to three prior cycles of hypomethylating agent-based therapy were given vosaroxin and azacitidine for a maximum of six cycles. The Phase 1 portion of the study was designed to determine the maximum tolerated dose and dose limiting toxicity of the combination. Other endpoints include best response, safety, tolerability, and event-free, progression-free, disease-free and overall survival.

Thirteen patients were enrolled in the dose-escalation phase and five of twenty planned patients have been enrolled in the expansion cohort to date. At the initial dose of 50 mg/m2/day vosaroxin, 2 of 6 patients experienced a DLT (grade 4 hyperbilirubinemia, and grade 4 neutropenia >42 days). The vosaroxin dose was de-escalated to 34 mg/m2/day, resulting in 1 of 6 patients with a DLT (grade 4 mucositis). Of the 18 patients enrolled to date, 16 completed ≥1 cycle and are evaluable for response. Best response for each patient was as follows: stable disease, n=3; stable disease with hematologic improvement (HI)-neutrophils, n=2; marrow complete remission (CR), n=4; marrow CR with HI-platelets; n=2; marrow CR with HI-neutrophils, n=1; marrow CR with HI-erythroid, n=1; and marrow CR with HI-platelets and neutrophils, n=1; and CR, n=1. One patient had progressive disease (PD). Of the 16 evaluable patients, 6 have proceeded to allogenic stem cell transplant and 3 are actively undergoing study treatment. The major non-hematologic toxicities of febrile neutropenia, infections, and mucositis were expected based on the disease population and prior experiences with vosaroxin.

"Hypomethlyating agents are the mainstay of treatment for myelodysplastic syndromes, yet these agents alone produce remissions in a minority of patients and are typically not curative," said Meagan A. Jacoby, M.D., Ph.D., Assistant Professor, Division of Oncology, Washington University School of Medicine, and principal investigator of the study. "The combination of vosaroxin and azacitidine show promising activity with response rates comparable or better than those generally observed with azacitidine alone. Additionally, the transplant rate observed is encouraging in this patient population with a median age of 66 years. We look forward to additional patient accrual and follow up from this study."

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Treatment-related mortality (TRM) score is a prognostic scoring system to predict risk of 30-day mortality with intensive treatment protocols in patients with newly diagnosed AML (Walter, 2011, J Clin Oncol 29:4417-4424). The "simplified TRM" score includes age, performance status (PS), platelet count, serum albumin, type of AML (secondary vs primary), white blood cell count, blast percentage in the peripheral blood, and serum creatinine. In a retrospective analysis, TRM and other criteria were used to evaluate risk of early mortality in patients with relapsed or refractory acute myeloid leukemia treated with vosaroxin plus cytarabine or placebo plus cytarabine in Sunesis’ randomized, double-blind, placebo-controlled Phase 3 VALOR trial.

A total of 705 patients from VALOR were included in the safety population (355 treated with vosaroxin/cytarabine and 350 treated with placebo/cytarabine). Rates of 30-day (7.9% vs 6.6%, respectively) and 60-day (19.7% vs 19.4%, respectively) mortality in VALOR were comparable between vosaroxin plus cytarabine and placebo plus cytarabine arms. Several individual baseline factors independently predicted risk of early mortality, including ECOG performance status, hemoglobin, bilirubin and albumin levels, intermediate or high bone marrow blasts, and prior myelodysplastic syndrome. The previously validated TRM score for predicting early mortality in newly diagnosed AML was also predictive of mortality in this relapsed/refractory population. Vosaroxin/cytarabine treatment and age were not significant predictors of early mortality.

"The rate of early mortality in patients treated for acute myeloid leukemia reflects a balance of efficacy and safety outcomes," said Dr. Jeffrey Lancet, Senior Member and Professor of Oncologic Sciences at the H. Lee Moffitt Cancer Center, Tampa, Florida. "The ability to assess increased risk of early mortality in this disease would provide valuable information in guiding treatment decisions. Based on this analysis, patient selection for future studies of vosaroxin and other intensive regimens in the AML setting may benefit from use of these predictive factors."

About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.
The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

On December 6, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported clinical data with denintuzumab mafodotin (SGN-CD19A; 19A) in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphocytic leukemia (B-ALL), presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015 (Press release, Seattle Genetics, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120410 [SID:1234508431]). Preclinical data from a novel antibody-drug conjugate (ADC) program called SGN-CD19B in B-cell malignancies will also be featured in an oral presentation. About 85 percent of non-Hodgkin lymphomas (NHL) are B-cell lineage, and CD19 is broadly expressed across all subtypes of B-cell malignancies. These two ADCs, 19A and SGN-CD19B, both target CD19 and utilize two of Seattle Genetics’ proprietary payloads, monomethyl auristatin F (MMAF) and a pyrrolobenzodiazepine (PBD) dimer, respectively. The company has initiated the first of two planned phase 2 trials of 19A in DLBCL and plans to advance SGN-CD19B into a phase 1 trial in 2016.

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"Data presented at ASH (Free ASH Whitepaper) from our 19A phase 1 trial in non-Hodgkin lymphoma show encouraging objective response rates, particularly in relapsed DLBCL patients, and a tolerability profile that we believe supports further investigation as part of novel regimens. Based on these data, we recently initiated a phase 2 trial in relapsed DLBCL, and plan to initiate a phase 2 trial in frontline DLBCL during 2016," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "CD19 is an attractive target for NHL, and there is a clear need for potent, safe and convenient therapies that can be used to improve outcomes for patients."

With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing ADCs, a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. More than 25 ADCs in clinical development utilize Seattle Genetics’ proprietary ADC technology.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refractory B-Lineage Non-Hodgkin Lymphoma (Abstract #182, oral presentation on Sunday, December 6, 2015 at 7:45 a.m.)

Data were reported from 62 patients with relapsed or refractory NHL, including 54 patients with DLBCL, five patients with mantle cell lymphoma and three patients with grade 3 follicular lymphoma. Of the 62 patients, 37 patients (60 percent) were refractory to their last therapy and 25 patients (40 percent) were relapsed. Sixteen patients (26 percent) had received a prior autologous stem cell transplant. The median age of patients was 65 years.

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and evaluate the safety and tolerability of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this study, patients receive 19A either every three weeks or every six weeks. Patients with stable disease or better are eligible to continue treatment with 19A. Key findings from an oral presentation by Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, include:

The maximum tolerated dose was not exceeded after escalating to 6 milligrams per kilogram (mg/kg) every three weeks.
Of the 60 patients evaluable for response, 23 patients (38 percent) achieved an objective response, including 14 patients (23 percent) with a complete remission and nine patients (15 percent) with a partial remission. Thirteen patients (22 percent) achieved stable disease and 24 patients (40 percent) had disease progression.

Antitumor activity appeared to be higher in relapsed patients. Of the 25 relapsed patients, 15 patients (60 percent) achieved an objective response, including 10 patients (40 percent) with a complete remission. In the 23 relapsed patients who responded, median duration of response was 47.1 weeks. Among all relapsed patients, median progression-free survival was 25.1 weeks and median overall survival was 56.7 weeks.

The most common adverse events of any grade occurring in more than 15 percent of patients were blurred vision (63 percent); dry eye (53 percent); fatigue, keratopathy and photophobia (39 percent each). Ocular symptoms were reported in more than 70 percent of patients. Symptoms were mostly Grade 1/2 and were managed with steroid eye drop treatment and dose modifications. Eighty-eight percent of patients with Grade 3 or 4 keratopathy experienced improvement and/or resolution within a median of five weeks.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Adults with Relapsed or Refractory B-Lineage Acute Leukemia (B-ALL) and Highly Aggressive Lymphoma (Abstract #1328, poster presentation on Saturday, December 5, 2015)

Data were reported from 72 adult patients with relapsed or refractory B-ALL and highly aggressive lymphomas, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 45 years and the median number of prior systemic therapies was two, with 20 patients (28 percent) having received a prior allogeneic stem cell transplant.

The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of 19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients received 19A in Schedule A (40 patients) at 0.3 to 3 mg/kg weekly or Schedule B (32 patients) at 4 to 6 mg/kg every three weeks. Key findings include:

Of the 56 B-ALL adult patients evaluable for response, six patients (19 percent) treated weekly achieved a composite complete remission (complete remission or complete remission with incomplete platelet or blood recovery) and nine patients (38 percent) treated every three weeks achieved a composite complete remission. The median duration of response was 27 weeks. Fifty-four percent of patients across both schedules achieved cytoreduction of greater than 50 percent.

In the ten patients with Philadelphia chromosome positive (Ph+) B-ALL, five patients (50 percent) achieved a complete remission and one patient (10 percent) had a partial remission. Ph+ B-ALL represents 20 to 30 percent of adult patients and carries a dismal prognosis, with higher rates of relapse and lower overall survival.

The maximum tolerated dose was not reached in patients treated weekly and was identified at 5 mg/kg in patients treated every three weeks.

The most common adverse events of any grade occurring in 25 percent or more of patients treated weekly (40 patients) or every three weeks (32 patients), respectively, were nausea (63 and 41 percent), fatigue (58 and 47 percent), fever (55 and 50 percent), headache (45 and 38 percent) and anemia (43 and 22 percent).

In the study, 43 patients (60 percent) developed ocular symptoms, of which 91 percent were Grade 1/2. These included blurred vision (39 percent), dry eye (25 percent) and photophobia (19 percent). Ocular symptoms were managed with steroid eye drop treatment and dose modifications. Keratopathy was observed in 34 patients, of whom 22 patients had Grade 3/4 events. The majority of patients with Grade 3/4 events had improvement or resolution with a median time of approximately four weeks.
The 19A phase 1 clinical trials are ongoing. Separately, a randomized phase 2 trial has recently initiated evaluating 19A in combination with R-ICE chemotherapy for second-line DLBCL. In addition, a phase 2 clinical trial in frontline DLBCL is planned to begin in 2016. More information about the 19A clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

SGN-CD19B, a Pyrrolobenzodiazepine (PBD)-Based Anti-CD19 Drug Conjugate, Demonstrates Potent Preclinical Activity Against B-Cell Malignancies (Abstract #594, oral presentation on Monday, December 7, 2015 at 11:45 a.m.)

A preclinical analysis evaluated the activity of SGN-CD19B, a new ADC consisting of an anti-CD19 antibody attached to a highly potent DNA binding agent called a PBD dimer, in multiple B-cell malignancy models. Data to be presented in an oral session demonstrate that SGN-CD19B exhibits antitumor activity against a broad panel of CD19-expressing B-cell malignancies, inducing durable tumor regressions and improved survival in multiple preclinical models of NHL and B-ALL. Based on these data, a phase 1 clinical trial evaluating SGN-CD19B in NHL is planned to start in 2016.

About Denintuzumab Mafodotin (SGN-CD19A)

Denintuzumab mafodotin (SGN-CD19A; 19A) is an ADC targeting CD19, a protein expressed broadly on B-cell malignancies. 19A is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cell-killing agent, monomethyl auristatin F (MMAF). The ADC is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

About Non-Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and NHL. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of NHL. According to the American Cancer Society, more than 71,000 cases of NHL were to be diagnosed in the United States during 2015 and more than 19,000 people would die from the disease.

About Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children. According to the American Cancer Society, more than 6,000 people will be diagnosed with ALL during 2015 and more than 1,400 would die from the disease.