Testicular cancer is the most common solid tumor among males in the 20- to 39-year age range. Moreover, testicular cancer has unique biological associations, clinical features, and psychosocial ...impacts that establish this tumor as a prototypic malignancy of young adults. The biology of testicular germ cell tumors after puberty is distinctive. Epidemiologic patterns of testicular cancer suggest etiologic factors that may be congenital, racial, and geographic. The clinical management of a cancer common among young adults, but rare among adults in general, requires expertise so as not to jeopardize the high rates of survivorship associated with modern therapy. The concurrent but separate development of staging, prognostic systems, and treatment recommendations between the fields of pediatric and adult oncology highlights the need for increased integration and cooperation across these subspecialties. The high rate of survival, combined with the need for long-term monitoring for relapse or late effects, demonstrates the challenge of delivering longitudinal care in this mobile and active young adult population.
Blinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). ...There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome–positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies.
•Dual Src/ABL inhibitors dasatinib and ponatinib inhibited blinatumomab-induced T-cell proliferation in vitro at nanomolar concentrations.•Potential immunomodulatory effects of targeted therapies should be taken into consideration before they are combined with immunotherapies.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: NHL is the 8 th most common cancer in the U.S. and exhibits poor survival, particularly among patients with disease resistant to chemotherapy. While CAR-T therapies are now available for ...patients with advanced disease, access to these therapies has been reported to be inequitable across varied sociodemographic populations. The Knight Cancer Institute is the only academic medical center and facility offering CART therapy in Oregon and nearby region, with the next closest center located 200 miles away. In this retrospective study, we identified baseline demographic and socioeconomic factors of NHL patients treated with CAR-T therapies at our institution, and factors associated with commercial versus investigational product used and overall survival. Methods: Adult patients with relapsed/refractory B-cell NHL referred to the OHSU Knight Cancer Institute for CAR-T therapy between Jan 2016 and May 2023 were included. Data collected included age, gender, race/ethnicity, zip-code, insurance type, disease type and status at time of treatment, and clinical trial participation. Zip-codes were used to estimate poverty level as defined by American Community Survey, rural-urban continuum codes and distance to the treatment center. Results: A total of 154 patients with median age of 62.7 years (range, 23.5-81.6) underwent CAR-T therapy for relapsed/refractory B-cell NHL with 4 commercial (86%) and 6 investigational products (14%). Of these, 43% were older than 65 years, 68% male and 14% self-identified as non-White (including Hispanic). Approximately 66% of those younger than 65 years were privately insured, while 82% of those over 65 years had Medicare. The majority of patients were from Oregon (85%), 12% from neighboring states of Southwest Washington and Idaho, and 2.6% from states outside of the Pacific Northwest region. About 29% of patients came from areas with poverty before the national level, 18% from non-Metropolitan areas (1.3% from remote rural areas). About 52% lived more than 30 miles away and 29% lived > 120 miles from the treatment center. Of the 22 patients receiving investigational products, 59% were males, 27% were older than 65, 18% were Non-white (including Hispanic), 46% had public insurance, 29% lived in areas below the national poverty level, 36% lived in non-Metropolitan areas (9% in remote rural areas), 55% were from areas > 60 miles away and 27% from areas > 120 miles from the treatment center. There were no statistical differences in utilization of commercial vs. research products for patients from racial/ethnic minorities or those living in areas > 30 miles, 60 or 120 miles from the transplant center, as compared to their counterparts. The proportion of patients receiving commercial products (vs. investigational product) was lower for patients from nonmetropolitan areas compared to metropolitan areas (71% vs. 88%, p=0.031) and for those living in areas below the national poverty level (76% vs. 90%, p=0.039), Table 1. With a median follow-up of 303 days (range, 30-1861) for survivors, the overall survival (OS) for the entire cohort is 65.8% (95 thCI, 62.6-68.9%). There were no statistically significant differences in overall survival for patients from racial/ethnic minorities, those living in non-metropolitan areas, living > 30 miles, 60 or 120 miles from the transplant center or in areas below the national poverty level, as compared to their counterparts. Conclusions: Although CAR-T access may vary by region, we have been able to offer this therapy to patients from socioeconomically diverse backgrounds in Oregon and nearby region. Our study highlights the importance of accounting for social determinants of health when implementing CAR-T therapy programs to optimize access to all patients. Participation in clinical trials may expand access to CART therapies, especially for those for which commercial products are less available.
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy of immature lymphocytes of either B cell or T cell origin. One particularly high -risk subset is Ph+ ALL, characterized by a ...translocation of chromosome 9 and 22, which generates the constitutively active BCR-ABL1 fusion tyrosine kinase capable of driving proliferation and survival of leukemic cells. Currently treatment options include multi-agent chemotherapy along with an ABL-specific tyrosine kinase inhibitor (TKI), though these regimens can lead to significant toxicity, particularly in older adults. Venetoclax is a potent and selective small molecule inhibitor of the B-cell lymphoma 2 (BCL-2) anti-apoptotic protein. Strong mechanistic and preclinical data have demonstrated strong synergistic activity between dasatinib and venetoclax I xenograft models and ex vivo patient samples, and provide an impetus to further explore the combination of BCR-ABL and BCL-2 inhibition in vivo. Based on these data, we designed a clinical trial to investigate the safety and preliminary efficacy of venetoclax in combination with the second generation TKI dasatinib in Ph+ ALL. Study Design and Methods This is an open label, Phase I/II investigator initiated trial evaluating the addition of venetoclax to dasatinib and steroids (with Rituximab in CD20+ patients). Phase I is the safety and dose-finding portion of the trial combining the BCL2 inhibitor venetoclax with dasatinib and steroids during the first 28 days of induction followed by dasatinib and venetoclax for the final 48 days of induction in newly diagnosed and relapsed Ph+ ALL and mixed phenotype acute leukemia (MPAL) patients, including patients with molecular only relapse. Primary inclusion criteria include a histologically confirmed diagnosis of Ph+ ALL or MPAL. Newly diagnosed Ph+ ALL or MPAL patients may not have received leukemia-directed therapy other than for steroids or hydrea, and relapsed patients must have not had prior dasatinib exposure. Key exclusion criteria include subjects with CML in myeloid blast crisis or Ph+ AML, ECOG < 2 and patients with a history of pleural effusions. n order to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), a Bayesian toxicity probability interval design applied to a pre-specified targeted dose limiting toxicity rate of 30%. Three dose cohorts investigating increasing doses of venetoclax will be enrolled. Once the RP2D dose has been identified, a Phase II expansion will examine preliminary efficacy of the combination. The primary endpoint is the rate of measureable residual disease (MRD) negative remission rate as assessed by both BCR-ABL RT-PCR and next generation sequencing (NGS) after induction. Secondary endpoints include relapse-free survival (RFS) and overall survival (OS). Correlative studies include BH3 profiling (measure of apoptosis) and ex vivo screening to dasatinib and venetoclax alone and in combination. Consolidation phase with blinatumomab plus dasatinib and venetoclax is planned for the cohort expansion group. Enrollment began in September 2022 and is expected to be complete by September 2025. This trial is registered at clinicaltrials.gov (NCT04872790).
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Overall cancer cure rates have risen over the last 30 years. Adolescent and young adult (AYA) oncology patients aged 15 to 39 have not shared in these successes as an age group, including those who ...fall into the younger age group of 15 to 19 years. The reasons for this deficit in survival improvement are manifold, but research has shown that an important factor is decreased enrollment in therapeutic clinical trials in this population versus younger patients. The paucity of adolescents treated in clinical trials is itself the result of several elements of the health care landscape in the United States. On the local level, these factors include referral patterns and facilities available; on the national level, related factors include the number of clinical trials available for this age group and health care provider education in the care of these patients. We examine the data available that have contributed to this deficit in the United States and offer broad strategies to address these shortcomings with the goal of improving outcomes in this underserved population.
The aim of this study was to evaluate the safety and efficacy of aprepitant when used prophylactically to prevent nausea and vomiting during cyclophosphamide-based conditioning regimens. The primary ...objective of this study was to determine if there was a difference in the number of emesis-free days in patients who received aprepitant as compared to those who received placebo. This prospective, randomized, double blind, placebo-controlled study was performed in 40 adult patients who received a cyclophosphamide-containing HSCT conditioning regimen. Twenty patients were randomized to receive aprepitant, ondansetron, and dexamethasone, and 20 were randomized to receive placebo, ondansetron, and dexamethasone. Complete response (CR) was defined as the absence of emesis and the absence of mild to moderate nausea. The average number of emesis-free days was 14.25 (standard deviation 1.48 days) in the aprepitant group compared to 12.45 days (standard deviation 2.16 days) for patients in the placebo group. Eight patients (40%) in the aprepitant group achieved CR as compared to four patients (20%) in the placebo group. In the setting of cyclophosphamide-containing conditioning regimens, the addition of aprepitant to a standard antiemetic regimen decreased the incidence of emesis as compared to placebo. Aprepitant was well tolerated.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose of Review
Outcomes for older adults with acute lymphoblastic leukemia (ALL) remain poor, and allogeneic hematopoietic stem cell transplant (HSCT) remains a potentially curative modality. ...However, benefits are offset by high rates of non-relapse mortality (NRM) in patients undergoing myeloablative conditioning (MAC) regimens. Reduced intensity conditioning (RIC) regimens can extend this therapy to adults who are unfit for MAC, although at the cost of higher relapse rates. In this review, we discuss evidence to support the usage of RIC regimens, controversies, and potential strategies to improve transplant outcomes going forward.
Recent Findings
Several novel therapies have recently been approved for the treatment of relapsed ALL and may play an important role in bridging adults with residual disease to RIC transplant. Assessing response to initial therapy via minimal residual disease (MRD) monitoring may determine which patients will derive the most benefit from allogeneic HSCT.
Summary
Reduced intensity allogeneic HSCT remains a potentially curative therapy that can be offered to older adults however challenges remain. Going forward, MRD testing and novel therapies may help better select which patients should proceed to transplant and assist in getting those patients to transplant with optimally controlled disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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