Wednesday, May 22, 2019

High-dose irradiation before HSCT and risk for malignant neoplasms

Study results shows that, survivors of allogeneic hematopoietic cell transplantation who underwent high-dose total body irradiation incurred nearly 8 times the risk for subsequent malignant neoplasms compared to general population.
Results showed the association to be strongly dose- and fractionation-dependent, and total body irradiation doses for nonmyeloablative conditioning posed no increased risk above that of myeloablative chemotherapy-only based regimens.
“The big takeaway is that people need to be aware of this risk,” Scott Baker, MD, director of the Fred Hutch survivorship program at Fred Hutchinson Cancer Research Center, said in a press release. “For those patients who received high-dose radiation, they need to be especially vigilant about following all the standard cancer prevention and screening recommendations. And younger patients, especially women, should talk to their doctor about starting screening for some cancers, such as breast, at an earlier age than recommended for this general population.”
In the retrospective study, Baker and colleagues evaluated 4,905 patients (57.4% men; 91.8% white) who underwent HSCT between 1969 and 2014 and had survived at least 1 year without subsequent malignant neoplasms. Patients had undergone the transplants for hematologic malignancies (n = 4,500) or nonmalignant conditions (n = 405). Median age at time of transplantation was 34.5 years (range 0.3-78.9),
Risk factors assessed by the researchers included sex, race, age at first transplant, diagnosis for transplant, stem cell source, regimen (including dose and fractionation) and development of graft-versus-host disease as a time-dependent covariate.
Eleven percent of the HSCT recipients (n = 499) developed a total of 581 subsequent malignant neoplasms at a median 10.3 years (range, 1-39.7) after HSCT.
With a median follow-up of 12.5 years (range, 1-42.11) among 1,709 surviving patients,  observed a 22% cumulative incidence of subsequent malignant neoplasms at 30 years post-HSCT.
Compared with SEER population rates matched for age, sex and calendar year, results showed a 2.8-fold (95% CI 2.6-3.1) increase in the standardized incidence ratio of subsequent malignant neoplasms.
The highest SIRs were for subsequent malignant neoplasms in the bones (28.8), oral cavity (13.8), skin (7.3), central nervous system (6) and endocrine organs (4.9).  (EARs) for subsequent malignant neoplasms per 1,000 person-years were seen in cancers of the breast (EAR = 2.2; 95% CI, 1.4-3), oral cavity (EAR = 1.5; 95% CI, 1.2-2) and skin (EAR = 1.5; 95% CI, 1.5-2).
Survivors exposed to either unfractionated (600 cGy-1,200 cGy-1,200 cGy) or high-dose fractionated (1,440 cGy-1750 cGy) total body irradiation had the highest incidence of subsequent malignant neoplasms. Those who received low-dose total body irradiation (200 cGy-450 cGy) demonstrated risk comparable to that of chemotherapy alone, albeit still twice that of the general population.
Patients aged 20 years and younger at the time of transplant had the highest risk for subsequent malignant neoplasms compared with age-matched members of the general population, although this risk decreased with longer follow-up in relation to transplant.
Patients aged 50 and older at the time of transplant showed sustained elevated SIRs over time, although follow-up beyond 20 years for these patients could not be accessed. Those aged 20 years or younger at the time of transplantation had a 2.28-times (95% CI, 1.31-3.96; P = 0.003) higher risk for subsequent malignant neoplasms than patients aged 50 years and older.
Risk for subsequent malignant neoplasms also appeared significantly higher among recipients of cord blood (HR = 3.02, 95% CI, 1.29-7.09) and peripheral blood stem cells (HR = 1.55; 95% CI, 1.16-2.07) vs. bone marrow, including after adjustment for acute and chronic GVHD.
“The ultimate goal for the transplant world is to find effective, nonradiation conditioning regimens, especially for children,” Baker said in the press release.
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Monday, May 20, 2019

Dogs detect human Cancers

Research suggests that dogs can detect many types of cancers in humans.
Like many other diseases, cancers leave specific traces, or odor signatures, in a person’s body and bodily secretions. Cancer cells, or healthy cells affected by cancer, produce and release these odor signatures.
Depending on the cancer type, dogs are able to detect these signatures in a person’s:
  • skin
  • breath
  • urine
  • feces
  • sweat
Dogs can detect these odor signatures and, with training, alert people to their presence. People refer to dogs that undergo training to detect certain diseases as medical detection dogs.
They detect some substances in very low concentrations, as low as parts per trillion, which makes their noses sensitive enough to detect cancer markers in a person’s breath, urine, and blood.
The fact that dogs can detect cancer has significant benefits for humans. Using dogs to detect and diagnose cancer is a low-risk, noninvasive method.
Medical detection dogs present few side effects and may offer advantages because they are mobile, can begin work quickly, and can trace an odor to its source.
They also have the potential for use in patient care settings or laboratories to identify cancer in tissue samples from people with suspected cancers.
Dogs’ abilities may also help with developing machines that can reliably detect odor signatures from cancer, such as electronic noses.
However, research is still underway and the effectiveness and reliability of canine cancer detection requires further research.
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Wednesday, May 8, 2019

Fast track designation to leronlimab for breast cancer

The FDA granted fast track designation to leronlimab for use in combination with carboplatin for the treatment of patients with CCR5-positive metastatic triple-negative breast cancer.
Leronlimab (PRO 140, CytoDyn Inc.) is an investigational humanized IgG4 monoclonal antibody that blocks CCR5, a cellular receptor believed to play key roles in tumor invasion and metastasis.
Agents that block CCR5 have been shown to block tumor metastases in laboratory and animal models of aggressive breast cancer and prostate cancer.
“This [fast track designation] is an important acknowledgement of the potentially paradigm-shifting therapy option in metastatic triple-negative breast cancer,” Richard Pestell, MD, PhD, vice chairman and chief medical officer of CytoDyn, said in a company-issued press release. “Currently, there are no enduring treatment options for [patients with metastatic triple-negative breast cancer] and we thank the FDA for recognizing the potential of leronlimab [in this setting].”
Enrollment is underway for a study designed to evaluate the agent for patients with metastatic triple-negative breast cancer.
CytoDyn expects to submit a biologics license application to the FDA this year for leronlimab as part of combination therapy for patients with HIV.
The CCR5 receptor also may play a key role in modulating immune cell trafficking to sites of inflammation.
CytoDyn is conducting a phase 2 study of leronlimab to support the concept that the CCR5 receptor on engrafted cells is key for the development of acute graft-versus-host disease. The FDA previously granted orphan drug designation to leronlimab for the prevention of GVHD.
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Tuesday, May 7, 2019

Biological age and breast cancer risk

Biological age, estimated by measuring DNA methylation, appeared to be a predictor for breast cancer risk, according to study results.
“[When looking] at a group of people who are all the same age, some may be perfectly healthy while others are not,” Jacob K. Kresovich, PhD, MPH, a postdoctoral fellow in the molecular and genetic epidemiology group of the National Institute of Environmental Health Sciences, said in a press release. “That variability in health may be better captured by biologic age than chronologic age.”
Because chronological age is a leading risk factor for breast cancer, Kresovich and colleagues hypothesized that biological age acceleration may be associated with increased breast cancer risk.
They measured baseline blood DNA methylation in 2,764 women enrolled in the Sister Study, including 1,566 women who developed breast cancer within years after baseline blood draw.
Researchers used three established methylation-based biological “clocks” and defined biological age acceleration for each woman by comparing estimated biological age with chronological age.
Results showed a significant association between biological age acceleration and increased risk for breast cancer (HR = 1.15; 95% CI, 1.07-1.23).
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Friday, May 3, 2019

Ibrutinib plus R-CHOP improves survival among younger patients with aggressive lymphoma subtype

The addition of ibrutinib to standard R-CHOP chemotherapy improved EFS, PFS and OS among patients aged younger than 60 years with untreated nongerminal center B-cell diffuse large B-cell lymphoma, according to results of a randomized, phase 3 study.
The combination, however, appeared associated with increased toxicity and resulted in worse outcomes among patients aged older than 60 years.
“The interaction between age and toxicity was surprising [because] it was not observed within the context of the phase 1 trial that we have published,” Anas Younes, MD, chief of the lymphoma service and Steven Greenberg chair at Memorial Sloan Kettering Cancer Center. “At the present time, there is no obvious biological explanation, but this will be addressed through planned extensive correlative studies. R-CHOP plus ibrutinib is not commonly given to patients with other types of lymphoma.”
DLBCL accounts for as many as 40% of all lymphoma cases, making it the most common form of lymphoma in the world. A previous phase 1 study appeared to demonstrate the safety of ibrutinib (Imbruvica; Pharmacyclics, Janssen) in combination with R-CHOP chemotherapy — which consists of rituximab (Rituxan; Genentech, Biogen) plus cyclophosphamide, doxorubicin, vincristine and prednisone — among patients with untreated B-cell lymphoma, including DLBCL.
Younes and colleagues specifically investigated whether ibrutinib improves the efficacy of R-CHOP in patients with untreated nongerminal center B-cell or activated B-cell diffuse large B-cell lymphoma.
Researchers randomly assigned 838 patients (median age, 62 years; range, 19-88; 53.3% men) to R-CHOP with ibrutinib at 560 mg daily (n = 419) or with placebo (n = 419) in a 21-day cycle for six or eight cycles, depending upon institutional guidelines.
Three-quarters of the patients (75.9%) had the activated B-cell DLBCL subtype.
EFS among the intent-to-treat population and patients with the activated B-cell subtype served as the study’s primary endpoint. Secondary endpoints included PFS, OS and safety.
Median follow-up was 34.8 months.
Results showed that the addition of ibrutinib to R-CHOP did not improve EFS compared with placebo and R-CHOP in the intent-to-treat population (HR = 0.93; 95% CI, 0.72-1.2) or the activated B-cell population (HR = 0.94; 95% CI, 0.7-1.27).
Ibrutinib also did not increase PFS (HR = 0.91; 95% CI, 0.71-1.18), OS (HR = 0.99; 95% CI, 0.71-1.38) or rates of overall response (89.3% vs. 93.1%) and complete response (67.3% vs. 68%) among the intent-to-treat population.
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Thursday, May 2, 2019

CAR T-cell therapy bb2121 shows promising efficacy, manageable toxicity in multiple myeloma

A chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen produced high response rates with manageable toxicity among patients with heavily pretreated relapsed or refractory multiple myeloma, according to results of a phase 1 study. “The adverse events noted in our study were very manageable, and we saw low rates of cytokine release syndrome and neurotoxicity,” Noopur Raje, MD,director of the Center for Multiple Myeloma at Massachusetts General Hospital and professor of medicine at Harvard Medical School.
“[The toxicity] was manageable to the extent that we are now thinking [forward to] outpatient settings. Response rates were high, but we did not see a plateauing of responses in very late-stage multiple myeloma.”
The CAR T-cell therapy bb2121 (Celgene, Bluebird Bio) has shown promise in preclinical studies for treatment of multiple melanoma, for which new therapies have prolonged survival but failed to prevent relapse.
Raje and colleagues reported results from the first 33 patients (median age, 60 years, range, 37-75; men, n = 21) with relapsed or refractory multiple myeloma who received bb2121 in the dose-escalation (n = 21) and dose-expansion (n = 12) phases of the open-label, multicenter trial. All patients had received at least three previous lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or were double refractory. All patients in the dose-escalation cohort and two patients in the dose-expansion cohort had tumor B-cell maturation antigen (BCMA) expression of 50% or greater.
After undergoing lymphodepletion with fludarabine and cyclophosphamide, patients received bb2121 as a single infusion at doses of 50 x 106, 150 x 106, 450 x 106 or 800 x 106 CAR-positive T cells in the dose-escalation phase and 150 x 106 to 450 x 106 CAR-positive T cells in the expansion phase.
Safety served as the primary endpoint. Data cutoff occurred 6.2 months after the last infusion.
Results showed an objective response rate of 85% (95% CI, 68.1-94.9), with 15 patients (45%) achieving a complete response, six of whom have since relapsed.
Median PFS was 11.8 months (95% CI, 6.2-17.8).
Sixteen patients with partial or complete responses appeared negative for minimal residual disease ( 10-4 nucleated cells).
All 33 patients experienced adverse events, including 28 (85%) who experienced a grade 4 event.
The most common grade 4 hematologic adverse events included neutropenia (n = 26), leukopenia (n = 13), thrombocytopenia (n = 10) and lymphopenia (n = 9). Grade 3 hematologic adverse events included anemia (n = 15), leukopenia (n = 6) and thrombocytopenia (n = 5).
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Waldenström macroglobulinemia progression

Researchers at Dana-Farber Cancer Institute have developed a classification system to determine whether a patient with asymptomatic Waldenström macroglobulinemia has a low, intermediate or high risk of developing symptomatic disease.
“This study is part of the efforts conducted by the Center for Prevention of Progression of Blood Cancers (CPOP) at Dana-Farber that aim to understand how blood cancers progress over time from early precursor stages,” Irene Ghobrial, MD, director of CPOP and the Michele & Steven Kirsch Laboratory for Waldenström’s Research, said in a press release. “We also try to identify biomarkers that predict cancer progression and provide these patients with early therapeutic interventions.”
Waldenström macroglobulinemia is a rare form of non-Hodgkin lymphoplasmacytic lymphoma of the bone marrow marked by production of monoclonal immunoglobulin M (IgM) protein —which gathers in the blood, weakens circulation and can cause complications.
Researchers studied 439 patients with asymptomatic Waldenström macroglobulinemia (median age at diagnosis, 61 years; range, 26-91; 62.2% men) who had been diagnosed and observed at Dana-Farber from 1992 to 2014 to determine risk factors for progression to symptomatic disease.
Progression to symptomatic Waldenström macroglobulinemia that required chemotherapy served as the primary endpoint.
Median follow-up was 7.8 years.
Seventy-two percent of patients (n = 317) progressed to symptomatic disease during the 23-year study period.
Median time to progression from diagnosis of asymptomatic disease to symptomatic disease was 3.9 years (95% CI, 3.2-4.6), and the probability of progression within 2 years of diagnosis was 30.8% (95% CI, 26.7-35.3).
Independent predictors of disease progression included IgM of 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration of 70% or greater, 2-microglobulin of 4 mg/dL or greater, and albumin levels less than 3.5 g/dL.
Using these four values as continuous measures, researchers trained and cross-validated a proportional hazards model to evaluate progression risk. The risk model stratifies patients into three groups: high risk (median time to progression [TTP], 1.8 years), intermediate risk (median TTP, 4.8 years) and low risk (median TTP, 9.3 years).
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