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Oncology Intelligence

Hodgkin's Lymphoma Therapeutics
Hodgkins lymphoma (HL) is a type of cancer that begins in lymphocytes. The main difference between HL and non-Hodgkins lymphoma (NHL) is in the specific lymphocyte each involves: if ReedSternberg cells (RSCs) are present, the diagnosis is generally HL, otherwise NHL.
HL is classified as a rare disease. There were approximately 9k new cases of HL and 1,200 deaths in the U.S. per year. For HL, the 5- and 10-year relative survival rates are 85% and 80%, respectively. Classic HL (cHL) accounts for about 95% of HL, while nodular lymphocyte predominant HL (nlpHL) accounts for about 5%. Treatment options for those patients who have failed first-line treatment are limited, and there is a significant unmet medical need for those patients.
The HL treatment market is currently $320 million/year and is likely to reach over a billion by 2020. This growth will is anticipated with a label extension to earlier lines of therapy for Adcetris and other premium priced biologic entering the market in HL.
Historic & ongoing clinical trials involving HL patients
Hodgkin's Lymphoma
Treatment
Most people with cHL receive some chemotherapy, followed by radiation therapy. Many different types of chemotherapy may be used for HL when it is first diagnosed. The most commonly used combination of drugs in the United States is called ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) followed by BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone).
R/R HL remains a therapeutic challenge. The majority of patients who are diagnosed with HL will be cured with primary treatment; however, approximately 10% of patients with localized cHL and approximately 30% with disseminated cHL relapse after primary conventional treatment with chemotherapy, alone or combined with radiotherapy.
If HL comes back after initial (first-line) treatment with ABVD or BEACOPP, there are several second-line treatments. Many of these treatments are given in preparation for an autologous stem cell transplant , but they can also be given to control the disease and its symptoms. These include ICE (ifosfamide, carboplatin, and etoposide), ESHAP or DHAP (etoposide or dexamethasone, methylprenisolone, high dose cytarabine, cisplatin (Platinol)), GVD, Gem-Ox, or GDP (gemcitabine, vinorelbine, doxorubicin; OR gemcitabine and oxaliplatin; OR gemcitabine, dexamethasone, and cisplatin, and brentuximab vedotin (Adcetris). Some of the other drugs prescribed for HL include chlorambucil approved for the palliative treatment, carmustine approved for R/R HL, lomustine for R/R HL, mechlorethamine for advanced HL, and prednisone. Rituximab may be used with chemotherapy to treat nlpHL. The aim of salvage therapy is to obtain cytoreduction and achieve chemosensitivity, which is always associated with better EFS after HDT and auto-transplantation. Recurrence of HL occurs in approximately 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge.
There has been a recent emergence of novel targeted agents for treatment of HL and NHL. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have shown significant promise in patients with R/R disease and in the frontline setting. RSC
Clinical Advances in Hematology & Oncology Volume 13, Issue 8 August 2015

RSCs express CD30 and CD15 on their cell surface, but not CD20 and CD45. PD-L1 is expressed on RS cell surfaces and can be targeted directly or through T-cells expressing PD-1. The JAK-STAT and PI3K pathways play an important role in the survival of RS cells and are deregulated in cHL.
Novel Antibodies and Antibody-Drug Conjugates Directed against Surface Antigens
There are a number of drugs antibody and ADC currently being investigated for NHL that are unlikely to be explored for HL. These include all CD20 targeted drugs since Rituxan is already an established treatment and can be used in combination with drugs in development. Additionally, CD20 is not expressed on the surface of RS cells, typical of HL. CD20 drugs in clinical development for NHL include: Obinutuzumab, ofatumumab. Inotuzumab ozogamicin is a CD22 targeting ADC tested for NHL. A phase 3 clinical trial of INO in combination with Rituxan or chemotherapy in R/R aggressive NHL did not demonstrated improved OS, failed to meet its primary objective, and was discontinued. MEDI-551, an anti-CD19 afucosylated mAb, in being tested for NHL, particularly for R/R DLBCL as a salvage therapy.
Rituximab, a chimeric mAb to CD20, is FDA approved for R/R indolent lymphoma and for maintenance therapy in B-cell NHL in combination with chemotherapy.
Brentuximab is an antibody-drug conjugate (ADC) targeting CD30, which is expressed in cHL and several types of NHL. It consists of an anti-CD30 mAb attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics proprietary technology. 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 (brentuximab) is FDA approved for cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, for cHL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and in accelerated approval for the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. It is being tested as an adjunct or replacement for chemotherapy before stem cell transplantation for patients with R/R HL. Adcetris currently accounts for 78% of the total market, and may make up 82% of sales by the end of 2024. The drug is expected to be approved for use in the treatment of newly diagnosed advanced-stage HL patients in 2018. Chemotherapy drugs used for R/R HL $500-2500/month, whereas rituximab and brentuximab costs $20k/month each because it is very complex and time consuming to produce biologics, particularly mAbs in therapeutic concentrations. The Australian PBAC noted that on the basis of inadequate cost-benefit, the medicine would not be made available more generally for the first-line treatment of R/R sALCL.
Other drugs in the same class include: polatuzumab, a CD79B (expressed on most B-cell malignancies) targeted therapy being tested in R/R NHL and DLBCL alone or in combination, SAR3419, a CD19 (expressed earlier than CD20 on B-cells) targeted therapy being tested in B-cell lymphoma, SGN-CD19A, targeting CD19 being tested for R/R B-cell NHL, blinatumomab, targeting both CD19 and CD3 being tested for R/R B-cell NHL and granted accelerated approval for R/R Ph- B-cell ALL, and lucatumumab targeting CD40 (expressed on most B-cell malignancies including HL) being tested for R/R HL and NHL.
Novel Antibodies Directed against Immune Checkpoint Proteins
CTLA-4 plays an important role in the immune checkpoint pathway by negatively controlling the function of regulatory T-cells leading to a decrease in antitumor immune response. PD-1 is another negative regulator of T-cell function which inhibits signaling pathways that activate T-cells when it interacts with PD-L1 and PD-L2. PD-1/PD-L1 is a particularly attractive target for HL since RS cells use the PD-1 pathway to bypass immune detection, and PD-1, PD-L1, and PD-L2, are over-expressed on RS cells. Amplification in HL also includes the JAK2, through the JAK2/STAT pathway, increases PD-1 ligand expression, making JAKs/STAT another promising HL target. Lymphocyte-activation gene-3 (LAG-3) is another immune checkpoint which is currently being targeted in a phase 1 study in hematologic malignancies, including lymphoma.
BMS and Merck. are expected to race to bring their newly approved anti-PD-1 therapies to the HL arena. BMSs nivolumab is slightly ahead of Mercks pembrolizumab in terms of clinical efficacy. Nivolumab (Opdivo), a PD-1 mAb, is FDA approved in Relapsed HL after auto-HSCT and post-transplantation vedotin. Pembrolizumab (Keytruda) is another humanized anti-PD-1 mAb. It is currently FDA approved for advanced (metastatic) (NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1 and is being tested for R/R hematologic malignancies, including R/R cHL. Atezolizumab (Tecentriq), the only PD-L1 FDA approved mAb, is approved for bladder cancer. It is currently being tested in a number of clinical trials for a variety of lymphomas, but not specifically for HL.
Other drugs in this class include pidilizumab, an anti-PD1 mAb, that has been tested for FL and DLBCL, MPDL3260A, a PD L1 targeted therapy that has been tested in combination with obinutuzumab in patients with R/R FL and DLBCL, and ipilimumab, a CTLA-4 targeting mAb that has been tested for R/r B-cell NHL as a monotherapy or in combination with rituximab.
Novel Small Molecule Inhibitors
Targeting specific pathways implicated in cancer has been the focus of oncology development for a number of years. For a complete discussion of targeted therapies see Pharmstatus Targeted Oncology.
Overexpression of aurora A kinase AAK has been identified in various malignancies, including lymphoma. Alisertib is an aurora kinase inhibitor being tested for R/R B and T cell NHL alone or in combinations. Targeted drugs in the lymphoma space include BTK inhibitor ibrutinib, being tested for NHL in combination or as a monotherapy. The BCL-2 family of proteins are regulators of apoptosis. Pro-survival BCL2 proteins are often overexpressed in lymphoma. Early agents targeting BCL2 were not as effective as expected, potentially because the BCL2 family of proteins is redundant. Recently, new agents have been developed which do not directly inhibit BCL-2 but instead act as mimics of BH3, which inhibit BCL-2 and related proteins. Navitoclax, a BH3 mimic, was tested for R/R NHL, where its lack of specificity resulted in thrombocytopenia, though in combination with rituximab most R/R CD20+ NHL patients achieved a PR. Another BH3 mimetic, venetoclax, has a higher specificity and is being tested in R/R NHL alone or in combination and dose limiting thrombocytopenia was not observed while the response rate was as high in 76% for R/R CLL/SLL.
Phosphoinositide 3-kinase (PI3K) is pathway involved in the B-cell receptor signaling cascade. PI3K has several tissue specific isoforms (alpha, beta, gamma, and delta). The PI3K5 signaling pathways are often overexpressed in B-cell malignancies. PI3K inhibitors being tested for NHL as a monotherapy or in combinations include idelalisib (PI3K5), duvelisib (PI3K5 and PI3Ky), copanlisib (PI3K5 and PI3Ka). TGR-1202, a PI3K5 inhibitor, is being tested in NHL and R/R HL in combination with BV. INCB04093, a PI3K8 inhibitor, is being tested in combination with INCB039110, a JAK1 inhibitor, against R/R B-cell malignancies, including cHL, with early promising results.
The Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases which recruitment STATs. Activated STATs translocate to the nucleus, where they activate transcription for a variety of processes including cell proliferation and immunity. The abnormal activation of the JAK-STAT pathway has been linked to many malignancies, including lymphomas. Pacritinib, a JAK2 inhibitor was tested for R/R HL and R/R NHL, and was well tolerated but showed an OR of 14%.
Competitive analysis for developing new HL therapies
5-force model
HL 5 forces
SWOT analysis
HL SWOT
References
Advani, R.H.; Buggy, J.J.; Sharman, J.P.; Smith, S.M.; Boyd, T.E.; Grant, B.; Kolibaba, K.S.; Furman, R.R.; Rodriguez, S.; Chang, B.Y.; et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with R/R B-cell malignancies. J. Clin. Oncol. 2013, 31, 88-94.
Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. The cHL microenvironment and its role in promoting tumour growth and immune escape. J Pathol. 2010;221(3):248263.
Armand, P. Immune checkpoint blockade in hematologic malignancies. Blood 2015, 125, 3393-3400.
Barr, P.M.; Sher, T.; Phillips, T.J.; Lebovic, D.; Zhou, L.; Pulini, J.; Spear, M.A.; Forero-Torres, A. A phase 2 trial of INCB040093 alone or in combination with INCB039110 in patients (pts) with R/R (r/r) cHL (cHL). J. Clin. Oncol. (ASCO Meeting Abstracts) 2015, 33, Abstract TPS8607.
Bartlett, N.L.; Farber, C.M.; Yasenchak, C.A.; Ansell, S.M.; Advani, R.H.; Knapp, M.H.; Fayad, L.; Kolibaba, K.S.; Patel-Donnelly, D.; Seetharam, M.; et al. Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (Pts) with high-intermediate/high-risk diffuse large B-cell lymphoma (DLBCL). J. Clin. Oncol. (ASCO Meeting Abstracts) 2015, 33, Abstract 8506.
Carbone, A.; Gloghini, A.; Castagna, L.; Santoro, A.; Carlo-Stella, C. Primary refractory and early-R/R HL: Strategies for therapeutic targeting based on the tumour microenvironment. J. Pathol. 2015, 237, 4-13.
Casali PG, Bruzzi P, Bogaerts J, Blay JY. Rare Cancers Europe (RCE) Consensus Panel. Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann Oncol. 2015 Feb;26(2):300306. [PMC free article] [PubMed]
Gaddipati H, Liu K, Pariser A, Pazdur R. Rare Cancer Trial Design: lessons from FDA Approvals. Clin Cancer Res. 2012 Oct 1;18(19):51725178. [PubMed]
Gagne JJ, Thompson L, O'Keefe K, Kesselheim AS. Innovative research methods for studying treatments for rare diseases: methodological review. BMJ 2014; 349 BMJ. 2014 Nov 24;349:g6802. [PMC free article][PubMed]
Green, M.R.; Monti, S.; Rodig, S.J.; Juszczynski, P.; Currie, T.; O'Donnell, E.; Chapuy, B.; Takeyama, K.; Neuberg, D.; Golub, T.R.; et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing HL and primary mediastinal large B-cell lymphoma. Blood 2010, 116, 3268-3277.
Jundt F, Anagnostopoulos I, Frster R, Mathas S, Stein H, Drken B. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood.2002;99(9):33983403.
Kppers R, Engert A, Hansmann ML. HL. J Clin Invest. 2012;122(10):34393447.[PMC free article]
Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 2012;30(7):679692.
Marinaccio C, Nico B, Maiorano E, Specchia G, Ribatti D. Insights in HL angiogenesis.Leuk Res. 2014;38(8):857861.
Phillips, T.J.; Forero-Torres, A.; Sher, T.; Magid Diefenbach, C.S.; Talpaz, M.; Scherle, P.A.; Schaub, R.; Zhou, L.; Pulini, J.; Leopold, L.; et al. Interim analysis of a phase I study of INCB040093, a PI3K5 inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor, in patients (pts) with R/R (r/r) B-cell malignancies. J. Clin. Oncol. (ASCO Annual Meeting) 2015, 33, Abstract 8520.
von Tresckow B, Diehl V. An update on emerging drugs for HL. Expert Opin Emerg Drugs. 2014;19(2):215224.
Weir SJ, DeGennaro LJ, Austin CP. Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership. Cancer Res. 2012;72(5):10551058.[PMC free article]
Younes, A.; Romaguera, J.; Fanale, M.; McLaughlin, P.; Hagemeister, F.; Copeland, A.; Neelapu, S.; Kwak, L.; Shah, J.; de Castro Faria, S.; et al. Phase I study of a novel oral janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: Evidence of clinical and biologic activity in multiple lymphoma subtypes. J. Clin. Oncol. 2012, 30, 4161-4167.
Clinical Advances in Hematology & Oncology Volume 13, Issue 8 August 2015
Clinical trial number NCT00848926 for "A Pivotal Open-Label Trial of Brentuximab Vedotin for Hodgkin Lymphoma" at ClinicalTrials.gov
Expert Rev Clin Pharmacol. 2015 Nov; 8(6): 661663. doi: 10.1586/17512433.2015.1088382
Blood. 2015 Sep 10; 126(11): 13941397. doi: 10.1182/blood-2015-07-660365 PMCID: PMC4592277; Preclinical activity of the repurposed drug auranofin in cHL
adcreview.com/tag/relapsed-or-refractory-hodgkin-lymphoma/
healthcare.globaldata.com/media-center/press-releases/pharmaceuticals/hodgkins-lymphoma-treatment-market-set-to-quadruple-to-14-billion-by-2024-says-globaldata
Society AC. American Cancer Society: Cancer Facts and Figures 2014 Atlanta, Ga2014. Available from: http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf.
www.mdpi.com/j ournal/pharmaceuticals; Novel Targeted Agents in Hodgkin and NHL Therapy
www.ncbi.nlm.nih.gov/pmc/articles/PMC4724195/Guidance for Industry
www.pharmpro.com/news/2015/12/hodgkins-lymphoma-market-leading-drug?cmpid=horizontalcontent
www.cancer.gov/about-cancer/treatment/drugs/hodgkin-lymphoma#1
www.cancercenter.com/hodgkin-lymphoma/types/
www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-what-is-hodgkin-disease
www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/HealthProfessional.
www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf.
www.cancer.net/cancer-types/lymphoma-hodgkin/treatment-options
www.mayoclinic.org/diseases-conditions/hodgkins-lymphoma/expert-answers/lymphoma/faq-20058546


News
Thursday, September 22, 2016 10:00 AM|Chen, R., Gopal, A. K., Smith, S. E., Ansell, S. M., Rosenblatt, J. D., Savage, K. J., Connors, J. M., Engert, A., Larsen, E. K., Huebner, D., Fong, A., Younes, A.|Blood CLINICAL TRIALS AND OBSERVATIONS|Labels: clinical trial, HL

Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Thursday, September 22, 2016 10:00 AM|Huang, Y.-C., Lin, S.-J., Lin, K.-M., Chou, Y.-C., Lin, C.-W., Yu, S.-C., Chen, C.-L., Shen, T.-L., Chen, C.-K., Lu, J., Chen, M.-R., Tsai, C.-H.|Blood LYMPHOID NEOPLASIA|Labels: NHL, HL

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV tonsils but not in EBV+ PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV+ and EBV DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV+ PTLD and DLBCL.

Thursday, September 15, 2016 10:00 AM|Kumar, A., Casulo, C., Yahalom, J., Schoder, H., Barr, P. M., Caron, P., Chiu, A., Constine, L. S., Drullinsky, P., Friedberg, J. W., Gerecitano, J. F., Hamilton, A., Hamlin, P. A., Horwitz, S. M., Jacob, A. G., Matasar, M. J., McArthur, G. N., McCall, S. J., Moskowitz, A. J., Noy, A., Palomba, M. L., Portlock, C. S., Straus, D. J., VanderEls, N., Verwys, S. L., Yang, J., Younes, A., Zelenetz, A. D., Zhang, Z., Moskowitz, C. H.|Blood CLINICAL TRIALS AND OBSERVATIONS|Labels: HL

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.

Thursday, September 15, 2016 7:48 AM|Manikandan Raman|Biotech|Attachments|Labels: PD-1/PD-L1, financial, HL

Seattle Genetics, Inc. (NASDAQ: SGEN) received a ratings bump from Goldman Sachs to Neutral from Sell after the brokerage revised its Adcetris U.S. sales estimates in 1L Hodgkin's lymphoma (HL) "to reflect greater market penetration per physician diligence."

"We model 40 percent penetration (vs. 19 percent prior) in 1L HL, which reflects significant uptake in Stage III–IV patients (~50 percent of the incident pool). This translates to $754 million in US peak sales (vs. $358 million prior) and may be conservative depending on the magnitude of treatment benefit (a large benefit may drive use ...

Full story available on Benzinga.com

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, HL
This phase I/II trial studies the side effects and best dose of brentuximab vedotin that can be combined with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin lymphoma that has come back (relapsed) or is not responding to treatment (refractory). Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving brentuximab vedotin together with an ifosfamide, carboplatin, and etoposide chemotherapy regimen may kill more cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, HL
This phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with gemcitabine hydrochloride and to see how well they work in treating younger patients with Hodgkin lymphoma that has returned or does not respond to treatment. Monoclonal antibodies, such as brentuximab vedotin, may find cancer cells and help kill them. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving brentuximab vedotin together with gemcitabine hydrochloride may kill more cancer cells.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, HL
This randomized phase III trial studies brentuximab vedotin and combination chemotherapy to see how well they work compared to combination chemotherapy alone in treating younger patients with newly diagnosed Hodgkin lymphoma. Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Drugs used in chemotherapy, such as doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if combination chemotherapy is more effective with or without brentuximab vedotin in treating Hodgkin lymphoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: clinical trial, HL
This open-label, randomized, 2-arm, multicenter, phase 3 study has the primary objective of comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma(HL)
Wednesday, September 14, 2016 11:10 AM|Mayo Clinic Cancer Center - Research news|Labels: clinical trial, HL
ROCHESTER, Minn. — A phase I clinical trial of nivolumab found that the immune-boosting drug is a highly effective therapy for Hodgkin’s lymphoma. The multi-institution study, led by Mayo Clinic, indicated that the drug was safe and led to an 87 percent response rate in patients who had failed on other treatments. Results of the [...]
Wednesday, September 14, 2016 11:10 AM|Daniel Benharroch, Shai Pilosof, Jacob Gopas, Itai Levi|Journal of Cancer|Labels: Bcl-2, HL

We recognized a few possible complications of classical Hodgkin lymphoma therapy in a cohort of 209 patients: 8 developed a primary refractory disease (primary progression), 36 showed an early relapse and 21 showed a late relapse. Sialyl-CD15 expression in Hodgkin-Reed-Sternberg cells was significantly more positive in primary refractory Hodgkin lymphoma, which confirms our previously published findings. Bcl-2 showed a significantly lower level of expression in primary refractory disease than in the other follow-up groups. This is in contrast with a previous finding of Bcl-2, associated with a poor prognosis in primary refractory illness. Another category of variables, old age and advanced stages, was significantly different in the various complications but this finding is probably to be expected. We could not demonstrate a difference between the sequels and the control group with regard to several clinical and immunohistochemical markers. Sialyl-CD15 and Bcl-2 expression, in contrast, were confirmed as prognostic factors, mainly of tumor progression into primary refractory disease.

Wednesday, September 14, 2016 7:55 AM|BUR, H., HAAPASAARI, K.-M., TURPEENNIEMI-HUJANEN, T., KUITTINEN, O., AUVINEN, P., MARIN, K., SOINI, Y., KARIHTALA, P.|Anticancer Research recent issues|Labels: HL

Background: Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors. Materials and Methods: We assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma. Results: Strong cytoplasmic KDM4B expression in the reactive cellular infiltrate and also in Reed-Sternberg (RS) cells predicted poor relapse-free survival (RFS) (p=0.020 and p=0.022, respectively) in patients with limited-stage disease. Strong KDM4B expression in RS cells was also related to B-symptoms (p=0.007) and advanced stage (p=0.024). Strong KDM4D expression in the cytoplasm of RS cells was also associated with poor RFS in limited-stage patients RFS (p=0.043) and, most significantly, in patients receiving involved-field radiotherapy (p=0.007). Conclusion: KDM4B and KDM4D expression may associate with an aggressive subtype of classical Hodgkin lymphoma and be linked with radioresistance.

Tuesday, September 13, 2016 11:38 PM|Simona Primerano, Roberta Burnelli, Elisa Carraro, Marta Pillon, Caterina Elia, Piero Farruggia, Alessandra Sala, Luciana Vinti, Salvatore Buffardi, Giuseppe Basso, Maurizio Mascarin, Lara Mussolin|Journal of Cancer|Labels: childhood cancer, HL

Levels of plasma cell-free DNA (cfDNA) of a large series of children with classical Hodgkin lymphoma (cHL) were evaluated and analyzed at diagnosis and during chemotherapy treatment in relation with clinical characteristics. CfDNA levels in cHL patients were significantly higher compared with controls (p=0.002). CfDNA at diagnosis was correlated with presence of B symptoms (p=0.027) and high erythrocyte sedimentation rate (p=0.049). We found that the increasing of plasma cfDNA after first chemotherapy cycle seems to be associated with a worse prognosis (p=0.049). Levels of plasma cfDNA might constitute an interesting non-invasive tool in cHL patients' management.

Tuesday, September 13, 2016 8:19 PM|Daniel Benharroch, Karen Nalbandyan, Irina Lazarev|Journal of Cancer (RSS 2.0)|Labels: HL

We have scrutinized a previously analyzed cohort of classical Hodgkin lymphoma patients for evidence of a CD20 over-expression. This was pursued in order to determine whether all the 24 (12.6%) CD20+++ patients had clinical and/or biological profiles which would warrant a separate consideration and treatment or would carry a different outcome from our 166 CD20 (-) classical Hodgkin lymphoma patients. Except for an older age and a significantly lower expression of non-sialyl-CD15 antigen, both previously described in classical Hodgkin lymphoma, no justification to exclude these CD20+++ patients from the cohort at large is apparent. We suggest that the generally accepted view to the contrary be revised. In addition, we propose alternative interpretations for the low expression of CD20 found in a majority of Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma.

Tuesday, September 13, 2016 4:00 PM|Santoro, Mazza, Pulsoni, Re, Bonfichi, Zilioli, Salvi, Merli, Anastasia, Luminari, Annechini, Gotti, Peli, Liberati, Di Renzo, Castagna, Giordano, Carlo-Stella|Journal of Clinical Oncology Current Issue|Labels: clinical trial, HL
Purpose

This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemcitabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL).

Patients and Methods

Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. Progression-free and overall survival were also evaluated.

Results

In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, respectively.

Conclusion

This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong rationale for further development of the BeGEV regimen.

Wednesday, August 31, 2016 11:00 PM|O’Malley, Dennis P.; Fedoriw, Yuri; Weiss, Lawrence M.|Applied Immunohistochemistry & Molecular Morphology - Current Issue|Labels: NHL, HL
imageBackground: The diagnosis of “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma” represents an indeterminate or equivocal decision in relation to management because there remain differences in the management of Hodgkin and non-Hodgkin lymphomas. We developed a scoring system for this group of lymphomas using markers that are traditionally associated with diagnosis of classical Hodgkin lymphoma (CHL) and immunophenotypic markers associated with the “B-cell program” expressed in normal B cells. Materials and Methods: This system emphasized known criteria used to diagnose CHL that are rare in B-cell lymphoma (BCL) [CD15+, CD45−, CD20− or weak/variable, PAX5+ (weak or moderate), CD79a−, OCT-2−/BOB.1− or OCT-2+/BOB.1− or OCT-2−/BOB.1+, EBV+] versus findings that are common in BCL in contrast to CHL (CD15−, CD45+, CD20+ strong, PAX5+ strong, CD79a+, OCT-2+/BOB.1+, EBV−). After a preliminary test trial, MUM1 staining was also added. Results associated with CHL were assigned a score of +1 and score associated with BCL were assigned a score of −1. In the final grading system, a maximum score of +6 is possible for CHL and −6 for BCL. Results: An initial series of 38 cases was evaluated using a proprietary system that allows analysis of multiple stains on individual cells in a single section. An additional 23 cases were evaluated with results blinded until after scoring was performed. In general there was high concordance among cases originally diagnosed as CHL with high scores (score +4 to +6). Cases originally diagnosed as gray zone lymphomas exhibited a broader range of scores (+3 to −4). Cases of BCLs had low scores (−3 to −6). Conclusions: The primary goal of this study was to create a scoring system that allows a cumulative quantitative measure of immunohistochemical markers, based on expected results to compare cases that might have overlapping features. In most cases, scores that trend to one extreme or another are likely representative of CHL or BCL and do not lie in the gray zone. This scoring system allows for practical resolution of many borderline cases and provide some guidance in difficult cases.
Wednesday, August 31, 2016 10:05 PM|Unknown Author|Cancer Discovery current issue|Labels: clinical trial, HL

According to survival results from a phase II trial of brentuximab vedotin, 34 patients with relapsed or refractory classic Hodgkin lymphoma had a complete response with this CD30-targeting antibody–drug conjugate; 13 remain in remission 5 years later.

Wednesday, August 31, 2016 11:19 AM|Wang, C., Wu, Z., Wang, Y., Guo, Y., Dai, H., Wang, X.-H., Li, X., Zhang, Y.-J., Zhang, W.-y., Chen, M.-X., Zhang, Y., Feng, K.-c., Liu, Y., Li, S.-X., Yang, Q.-M., Han, W.|Clinical Cancer Research Online First Articles|Labels: clinical trial, HL

Purpose:Relapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory HL. Experimental Design:Patients with relapsed or refractory HL received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative Polymerase Chain Reaction. Results:Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions, and received a mean of 1•56x10 CAR-positive T cell per kg (SD 0.25, range 1•1-2•1) in total during infusion. CART-30 cell infusion was tolerated, with grade {greater than or equal to}3 toxicities occurring only in 2 of 18 patients. Of 18 patients, seven achieved partial remission, six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions, and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites, and reduction of the expression of CD30 in tumors. Conclusions:CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment.

Sunday, August 14, 2016 10:05 PM|Le, K.–S., Thibult, M.–L., Just–Landi, S., Pastor, S., Gondois–Rey, F., Granȷeaud, S., Broussais, F., Bouabdallah, R., Colisson, R., Caux, C., Menetrier–Caux, C., Leroux, D., Xerri, L., Olive, D.|Cancer Research recent issues|Labels: NHL, HL
The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25highCD127low/neg Tregs in FL tissues. These Tregs comprised activated ICOS+ Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25highFoxP3high Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648–60. ©2016 AACR.
Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: PD-1/PD-L1, biomarker diagnostic, HL

The FDA has conditionally approved atezolizumab, the first PD-L1 inhibitor, for metastatic urothelial carcinoma, along with a companion diagnostic, the Ventana PD-L1 (SP142) assay. The agency has also expanded nivolumab's indications to include classical Hodgkin lymphoma, making this PD-1 inhibitor the first to be approved for a hematologic malignancy.

Sunday, July 31, 2016 11:00 PM|Roberts, Kenneth B.; Younes, Anas; Hodgson, David C.; Advani, Ranjana; Dabaja, Bouthaina S.; Dhakal, Sughosh; Flowers, Christopher R.; Ha, Chul S.; Hoppe, Bradford S.; Mendenhall, Nancy P.; Metzger, Monika L.; Plastaras, John P.; Shapiro, Ronald; Smith, Sonali M.; Terezakis, Stephanie A.; Winkfield, Karen M.; Constine, Louis S.; Expert Panel on Radiation OncologyLymphoma|American Journal of Clinical Oncology - Most Popular Articles|Labels: HL
imageThese guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Wednesday, July 27, 2016 11:11 AM|BERNIG, T., RITZ, S., BRODT, G., VOLKMER, I., STAEGE, M. S.|Anticancer Research recent issues|Labels: HL

Background: Glutathione-S-transferases (GSTs) are associated with multidrug resistance of tumor cells and are involved in drug detoxification and control of apoptosis. We analyzed the impact of GSTs on apoptosis of Hodgkin's lymphoma (HL) cells. Materials and Methods: Expression of GST isoforms in HL cell lines was assessed by analysis of DNA microarray data and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of the GST inhibitor ethacrynic acid (EA) on HL cell survival was analyzed in vitro. Results: DNA microarray analysis and qRT-PCR analysis demonstrated higher expression of GST isoforms in chemoresistant HL cells. Therefore, GSTs may contribute to chemoresistance of HL cells. Incubation of GST-expressing chemoresistant L-1236 HL cells with EA significantly enhanced the activity of cisplatin against these cells. Conclusion: Our data suggest that the combined treatment with chemotherapy and GST inhibitors such as EA might be an interesting option for patients with chemoresistant HL.

Dateline City:
KENILWORTH, N.J.

Findings Support Initiation of Phase 3 Pivotal Study (KEYNOTE-204) Evaluating KEYTRUDA Versus Brentuximab Vedotin in Relapsed or Refractory cHL

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the first-time presentation of findings from KEYNOTE-087, the phase 2 study investigating the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). These data will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago from 8:00 – 11:30 a.m.

Language:
English
Contact:

Merck
Media:
Pamela Eisele, 267-305-3558
or
An Phan, 908-255-6325
or
Investors:
Teri Loxam, 908-740-1986
or
Justin Holko, 908-740-1879

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Thursday, April 28, 2016 4:59 AM|Unknown Author|Financial News|Labels: financial, HL
Dateline City:
NEW YORK
  • Increases First Quarter Revenues 9% to $4.4 Billion
  • Posts First Quarter GAAP EPS of $0.71 and Non-GAAP EPS of $0.74
  • Achieves Significant European Regulatory Milestones in Immuno-Oncology
    • Opdivo Approved for Previously Treated Advanced Renal Cell Carcinoma
    • Expanded Use of Opdivo to Include Previously Treated Metastatic Non-Squamous Non-Small Cell Lung Cancer
    • Positive Advisory Opinions for Opdivo + Yervoy Regimen and Empliciti
    • Validation of Application for Opdivo in Classical Hodgkin Lymphoma
  • Announces Opdivo Granted Breakthrough Therapy Designation for Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck, and Priority Review in Classical Hodgkin Lymphoma from the FDA
  • Presents Significant New Data on Immuno-Oncology Portfolio at AACR
  • Increases 2016 GAAP EPS Guidance Range to $2.37 - $2.47 and Non-GAAP EPS Guidance Range to $2.50 - $2.60

NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today reported results for the first quarter of 2016, which were highlighted by strong sales for Opdivo, Eliquis and our hepatitis C franchise along with significant regulatory milestones and key data in Immuno-Oncology.

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English
Contact:

Bristol-Myers Squibb Company
Communications:
Ken Dominski, 609-252-5251
ken.dominski@bms.com
or
Investor Relations:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill Szablewski, 609-252-5894
william.szablewski@bms.com

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BMY
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NYSE

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Dateline City:
KENILWORTH, N.J.

Fourth Designation for KEYTRUDA Follows Breakthrough Status in Advanced Melanoma, Non-Small Cell Lung Cancer, and Colorectal Cancer

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (cHL). This is the fourth Breakthrough Therapy Designation granted for KEYTRUDA.

Language:
English
Contact:

Merck
Media:
Pamela Eisele, 267-305-3558
An Phan, 908-255-6325
or
Investors:
Teri Loxam, 908-740-1986
Justin Holko, 908-740-1879

Ticker Slug:
Ticker:
MRK
Exchange:
NYSE

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