Chemotalk Newsletter

Chemotalk Newsletter, Vol. 112 August 1, 2017

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Here's just a fraction the news for August:

CAR-T CELL THERAPY GIVEN GREEN LIGHT BY ODAC FOR B-CELL ACUTE LYMPHOBASTIC LEUKEMIA

By John Schieszer

    It looks like 2017 will be a transformative year for CAR-T therapy. The US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of CTL019 (tisagenlecleucel) on July 12, 2017 for the treatment of relapsed or refractory pediatric and young adult patients with B-CELL ACUTE LYMHOBLASTIC LEUKEMIA (ALL).

    Tisagenlecleucel is an investigational chimeric antigen receptor (CAR) T cell therapy by Novartis. The advisory committee hearing was the last major regulatory milestone before the agency decides in September whether to approve the treatment, which would make this the first-ever commercially approved CAR-T cell therapy. The committee¹s unanimous positive vote bodes well for this gene therapy approach.

    Effective treatment options for patients with relapsed/refractory ALL are limited. In pediatric and young adult patients with B-cell ALL who relapse or are refractory to treatment, the survival rates are very low. "We know firsthand from treating children and young adults with relapsed/refractory B-cell ALL that they desperately need innovative medicines that provide a new approach to managing this aggressive disease," said Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine at Pennsylvania University and Director of the Cancer Immunotherapy Frontier Program, both in Philadelphia, Pennsylvania.

    CTL019 was first developed by the University of Pennsylvania and uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular responses. This approach in clinical studies has been associated with long-lasting remissions in relapsed and treatment refractory patients.

    CAR-T is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient's blood and reprogrammed in the manufacturing facility to create T cells that are genetically coded to express a chimeric antigen receptor to recognize and fight cancer cells and other B-cells.

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ADHERENCE TO DISTRESS SCREENING PROTOCOLS LACKING

By Leah Lawrence

    Adherence to screening protocols for routine distress screening at cancer centers resulted in fewer emergency department visits and hospitalizations in the 2-month period after the screening, according to the results of a study published in the Journal of the National Comprehensive Cancer Network.

    According to Brad Zebrack, PhD, MSW, MPH, from the University of Michigan School of Social Work and the University of Michigan Comprehensive Cancer Center, utilization of distress screening protocols, such as the National Comprehensive Cancer Network Distress Thermometer, has the ability to uncover incapacitating conditions that, left untreated, could have an incredibly negative effect on patient outcomes.

    "Appropriate screening and identification of distress would flag a referral to a social worker, whose clinical assessment would uncover the cause of the patient¹s distress and lead to clinical engagement and delivery of an appropriate, evidence-based intervention, complementary to clinical treatment," Zebrack said.

    In the study, oncology social workers at Commission on Cancer­accredited cancer programs reviewed the electronic health records (EHRs) for their programs during a 2-month period in 2014. Adherence to distress screening protocols were based on documentation within the EHR that showed that screening and an appropriate clinical response had occurred.

    The review of 8,409 EHRs from 55 centers showed an overall adherence rate of 62.7%. Adherence rates varied by institution and patient characteristics. For example, adherence was higher in community cancer programs (76.3%) compared with NCI-Designated Cancer Centers (43.3%). High rates of adherence were found in patients identified as black/African American (70.5%), and the lowest rates were seen in patients of American Indian/Alaska Native/Native Hawaiian/Pacific Island descent (45.7%).
Additionally, patients aged 15 to 39 years were significantly less likely to be in adherence for screening compared with older patients.

    "Particularly concerning is the finding that documentation of psychosocial screening is lacking in 1 of every 3 cases in this representative sample," the researchers wrote. "The absence of these clinical data can compromise the ability of oncology care providers to know whether patients are receiving the psychosocial care and support they need when they need it."

    When screening protocols were followed, 12.8% of patients reported to have used the emergency department compared with 15.7% of patients for whom protocol was not followed. Similarly, when protocol was followed, 18.6% of patients were hospitalized at least once in the subsequent 2 months compared with 23.5% of patients who were not screened.

    After controlling for independent effects of institutional or patient characteristics, the risk ratio for emergency department use indicated an 18% reduction in the likelihood of use among patients in adherence with the protocol (0.82). The risk ratio for hospitalization indicated a 19% reduction in the likelihood of use seen with adherence (0.81).

    The researchers noted that "the findings are not intended to suggest that screening adherence causes reductions in service utilization, because the study is limited by its cross-sectional design, modest rates of missing data (although comparable to studies using EHRs), lack of detailed patient data, and variation across participating cancer programs in terms of the complexity of cases treated."

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GERM CELL TUMORS

By Bryant Furlow

    A meta-analysis of data from five genome-wide association studies has revealed eight newly identified gene loci associated with the risk of developing TESTICULAR GERM CELL TUMORS (TGCT), according to a report published in Nature Genetics. The analysis was conducted by the International Testicular Cancer Consortium and an international team of researchers.

    "Our findings substantially increase the number of known susceptibility genes associated with TGCT," said a senior study author, Peter A. Kanetsky, PhD, MPH, chair of the Department of Cancer Epidemiology at the H. Lee Moffitt Cancer Center in Tampa, Florida. "This moves the field closer to a comprehensive understanding of the underlying genetic architecture and development of the disease."

    Men with Northern European ancestry are more likely to be diagnosed with TGCT. In addition, men whose fathers or brothers are diagnosed with TGCT have a dramatically higher risk of developing the disease themselves.

    The team analyzed genome-wide association data from five testicular cancer studies representing 3,558 men with TGCT and 13,970 controls.
Previously identified gene variant associations help to explain an estimated 37% of the observed heritable risk between fathers and sons, the study team estimated.

    They also identified eight previously-unreported loci identified with increased TGCT risk.  The implicated loci are "biologically plausible" actors in testicular cancer because they are involved in sperm development.
These genes might represent targets for drug development.

    The risk alleles might also help to identify men who should be screened for TGCT, the study authors suggested.

    Testicular cancer is a rare malignancy, with fewer than 8,900 cases diagnosed annually in the United States. The vast majority of these cases are TGCTs occurring in men younger than 40 years. TGCT incidence rates vary geographically and among ethnicities, and have increased over time in recent decades.

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HIGH-DOSE CHEMOTHERAPY PLUS TRANSPLANT NOT RECOMMENDED FOR DLBCL

By Leah Lawrence

    Patients with high-risk DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) had a reduced risk of treatment failure when assigned to an abbreviated course of rituximab-dose-dense chemotherapy plus high-dose cytarabine, mitoxantrone, and dexamethasone (R-MAD) plus carmustine, etoposide, cytarabine, and melphalan (BEAM) plus autologous stem cell transplantation compared with a full course of rituximab-dose-dense chemotherapy, according to a study published in Lancet Oncology. However, this treatment regimen did not result in an improvement in overall survival.

    "On the basis of these results, early consolidation with high-dose chemotherapy and autologous stem cell transplantation cannot be recommended, and R-CHOP [rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone] should remain the standard treatment for DLBCL in patients with poor prognosis," wrote Annalisa Chiappella, MD, of the department of hematology at Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino in Turin, Italy, and colleagues.

    The study compared two different dose levels of R-CHOP: a full course of rituximab-dose-dense chemotherapy (no transplant group) compared with an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD and BEAM plus stem cell transplantation. The study included 399 patients age 18 to 65 years with untreated high-risk DLBCL. The patients were randomly assigned to one of four arms: R-CHOP delivered in a 14-day cycle (R-CHOP-14) for 8 cycles; high-dose R-CHOP-14 (R-MegaCHOP-14) for 6 cycles; R-CHOP-14 for 4 cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation; or R-MegaCHOP-14 for 4 cycles followed by R-MAD plus BEAM and autologous stem cell transplantation. The primary endpoint was failure-free survival at 2 years.

    With a median follow-up of 6 years, the 2-year failure-free survival rate for the whole population was 66%, the overall survival rate was 82%, and the progression-free survival rate was 69%. Patients assigned to transplant had significantly improved 2-year failure-free survival rates (71% vs 62%; hazard ratio [HR], 0.65; 95% CI, 0.47­0.91; P = .012) compared with patients who did not receive a transplant. However, there was no significant difference in 5-year overall survival between the transplant groups.

    The researchers suggested several reasons why the difference in failure-free survival did not translate into a difference in overall survival as it has in other trials of DLBCL. First, this study did not include patients older than 65 years, suggesting that failure-free survival may not be a valid surrogate endpoint in this younger patient population. In addition, a difference in failure-free survival with transplant was only seen in patients with intermediate-high risk, which could have lowered the power of the comparison.

    There was no significant difference in failure-free survival between patients who received R-CHOP-14 and R-MegaCHOP-14 (67% vs 66%). Based on this, the researchers wrote, "The findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with DLBCL who are at high risk."

    Grade 3 or worse hematologic events occurred in 92% of patients assigned to transplant and 68% of patients in the no-transplant group. The most common nonhematologic adverse event was gastrointestinal (25% of transplant patients vs 10% with no transplant).

    "The addition of novel drugs such as lenalidomide, ibrutinib, bortezomib, and others to standard R-CHOP regimens has been reported in phase I or II studies with promising results in high-risk patients as well, leading to ongoing phase III randomized trials to assess the efficacy of these strategies," the researchers noted. "While awaiting the results of these randomized studies, the standard treatment in patients with DLBCL at intermediate-high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen."

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See you next month...

And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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