Aaron S. Rosenberg

Imatinib and prostate cancer: lessons learned from targeting the platelet-derived growth factor receptor

Introduction: The platelet derived growth factor (PDGF) signaling pathway has been implicated in both epithelial and stromal mechanisms of prostate cancer progression and postulated as a target for therapy in bone metastases. Imatinib mesylate is a potent inhibitor of the platelet-derived growth factor receptor (PDGFR) and its activity has been tested in preclinical models and in Phase I and II clinical trials. Areas covered: This review summarizes the preclinical data on PDGF/PDGFR in prostate cancer, and reviews the clinical and correlative data using imatinib as a PDGFR inhibitor. Expert opinion: To date, the use of imatinib to treat men with prostate cancer has been ineffective, and PDGFR inhibition may in fact accelerate advanced forms of the disease and antagonize taxane efficacy. Given the major discordance between preclinical models and clinical experimentation, an accurate understanding of the PDGF-regulated interactions between metastatic prostate cancer and the bone micro-environment is evidently warranted. Correlations of pharmacodynamic monitoring of imatinib-induced PDGFR inhibition with progression-free and overall survival outcomes have led to the hypothesis that PDGF may function as a homeostatic factor in bone metastases. Recent laboratory studies defining PDGFR-regulated pericytes as gatekeepers of metastases may relate to these clinical observations.

Increased incidence of VTE in sickle cell disease patients: Risk factors, recurrence and impact on mortality

Previous reports show increased incidence of venous thromboembolism [VTE, deep‐vein thrombosis (DVT) and pulmonary embolus (PE)] in sickle cell disease (SCD) patients but did not account for frequency of hospitalization. We determined the incidence of VTE in a SCD cohort versus matched controls. For SCD patients, risk factors for incident VTE, recurrence and the impact on mortality were also determined. Among 6237 patients with SCD, 696 patients (11·2%) developed incident‐VTE: 358 (51·6%) had PE (±DVT); 179 (25·7%) had lower‐extremity DVT only and 158 (22·7%) had upper‐extremity DVT. By 40 years of age, the cumulative incidence of VTE was 17·1% for severe SCD patients (hospitalized ≥3 times a year) versus 8·0% for the matched asthma controls. Amongst SCD patients, women (Hazard ratio [HR] = 1·22; 95% confidence interval [CI]: 1·05–1·43) and those with severe disease (HR = 2·86; 95% CI: 2·42–3·37) had an increased risk of VTE. Five‐year recurrence was 36·8% in patients with severe SCD. VTE was associated with increased risk of death (HR = 2·88, 95% CI: 2·35–3·52). In this population‐based study, the incidence of VTE was higher in SCD patients than matched controls and was associated with increased mortality. The high incidence of recurrent VTE in patients with severe SCD suggests that extended anticoagulation may be indicated.

Second Primary Malignant Neoplasms and Survival in Adolescent and Young Adult Cancer Survivors

Importance Although the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age. Objective To assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (<15 years) and older adult (≥40 years) patients with the same SPMs. Design, Setting, and Participants This was a population-based, retrospective cohort study of patients with cancer in 13 Surveillance, Epidemiology and End Results regions in the United States diagnosed from 1992 to 2008 and followed through 2013. Data analysis was performed between June 2016 and January 2017. Main Outcomes and Measures Five-year relative survival was calculated overall and for each cancer occurring as a PM or SPM by age at diagnosis. The impact of SPM status on cancer-specific death was examined using multivariable Cox proportional hazards regression. Results A total of 15 954 pediatric, 125 750 AYAs, and 878 370 older adult patients diagnosed as having 14 cancers occurring as a PM or SPM were included. Overall, 5-year survival after an SPM was 33.1% lower for children, 20.2% lower for AYAs, and 8.3% lower for older adults compared with a PM at the same age. For the most common SPMs in AYAs, the absolute difference in 5-year survival was 42% lower for secondary non-Hodgkin lymphoma, 19% for secondary breast carcinoma, 15% for secondary thyroid carcinoma, and 13% for secondary soft-tissue sarcoma. Survival by SPM status was significantly worse in younger vs older patients for thyroid, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, soft-tissue sarcoma, and central nervous system cancer. Adolescents and young adults with secondary Hodgkin lymphoma (hazard ratio [95% CI], 3.5 [1.7-7.1]); soft-tissue sarcoma (2.8 [2.1-3.9]); breast carcinoma (2.1 [1.8-2.4]); acute myeloid leukemia (1.9 [1.5-2.4]); and central nervous system cancer (1.8 [1.2-2.8]) experienced worse survival compared with AYAs with the same PMs. Conclusion and Relevance The adverse impact of SPMs on survival is substantial for AYAs and may partially explain the relative lack of survival improvement in AYAs compared with other age groups. The impact of a particular SPM diagnosis on survival may inform age-specific prevention, screening, treatment, and survivorship recommendations.

Investigation into the interference of the monoclonal antibody daratumumab on the free light chain assay.

OBJECTIVES Recently monoclonal antibody therapy has been introduced in the treatment of multiple Myeloma (MM). One such efficacious therapy is the anti-CD38 monoclonal antibody, daratumumab (Dara). Since it is an Ig-G-kappa it can interfere with both the serum protein electrophoresis and immunofixation electrophoresis (IFE). The free light chain (FLC) assay is also useful in the diagnosis and therapeutic monitoring of MM. Hence we tested the effect of Dara on the FLC assay. METHODS 30 serum samples from patients with known IgG-kappa (n=20) and non-IgG-kappa M -proteins (n=10) were spiked with Dara at a final concentration of 1.0mg/mL and the FLC performed on samples. On a further 20 samples we performed IFE to determine the migration of Dara. RESULTS On IFE, Dara migrated in the same area of the gamma zone. In the 30 samples in which we assayed FLC there was no significant differences in levels of kappa, lambda and the ratio of kappa to lambda between untreated and Dara-spiked samples. CONCLUSION Whilst Dara can interfere with the IFE to determine clinical responses the FLC assay can be useful in patients who have abnormal FLC ratios prior to Dara therapy to determine responses especially in IgG-kappa Myeloma.

Hodgkin lymphoma post-transplant lymphoproliferative disorder: A comparative analysis of clinical characteristics, prognosis, and survival.

Hodgkin lymphoma post‐transplant lymphoproliferative disorder (HL‐PTLD) is an uncommon PTLD with unclear prognosis and differences between HL‐PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL‐PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL‐SEER). Overall survival (OS) and disease‐specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL‐PTLD diagnosis was 88 months. When compared with HL‐SEER, patients with HL‐PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P < 0.001), Caucasian (81% vs. 70%, P = 0.02), and had extranodal disease (42% vs. 3%, P < 0.001). Five‐year OS for patients with HL‐PTLD was 57% versus 80% for HL‐SEER (P < 0.001); DSS was also inferior (P < 0.001). For patients with HL‐PTLD, the use of any chemotherapy was associated with decreased hazard of death (HR = 0.36, P < 0.001). Furthermore, patients who received no chemotherapy or nontraditional HL regimens had increased hazard of death (aHR = 2.94, P = 0.001 and 2.01, P = 0.04) versus HL‐specific chemotherapy regimens. In multivariable analysis, advanced age and elevated creatinine were associated with inferior OS (aHR = 1.26/decade P < 0.001 and 1.64/0.1 mg/dL increase P = 0.02). A prognostic score based on the number of these adverse factors (0, 1, 2) was associated with 10‐year OS rates of 79%, 53%, and 11%, respectively (P < 0.001). Altogether, HL‐PTLD patients have inferior survival when compared with HL‐SEER. Furthermore, treatment with HL‐specific chemotherapy was associated with improved OS, whereas age and creatinine identified patients with markedly divergent survival. Am. J. Hematol. 91:560–565, 2016.

Secondary acute lymphoblastic leukemia is a distinct clinical entity with prognostic significance

The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988–2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45–1.79). Hematologic malignancies (SIR 5.57, 4.38–6.98) and IR-solid tumors (SIR 2.11, 1.73–2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16–1.63)) and this effect was more pronounced among younger patients (age<40 years: aHR 4.80 (3.15–7.30); age⩾40 years: aHR 1.40 (1.16–1.69)) (interaction P<0.001). This population-based study demonstrates that s-ALL is a distinct entity that occurs after specific malignancies and carries a poor prognosis compared with de novo ALL, particularly among patients <40 years of age.

Breast cancer and thrombosis: timing matters

In this issue of Blood , [Walker et al][1] estimate venous thromboembolism (VTE) rates associated with current breast cancer treatments in time windows before, during, and following treatment.[1][2] ![Figure][3] Absolute and adjusted relative rates (RRadj) of VTE associated with surgery,

Incidence and Evaluation of Incidental Abnormal Bone Marrow Signal on Magnetic Resonance Imaging

Purpose. The increased use of magnetic resonance imaging (MRI) has resulted in reports of incidental abnormal bone marrow (BM) signal. Our goal was to determine the evaluation of an incidental abnormal BM signal on MRI and the prevalence of a subsequent oncologic diagnosis. Methods. We conducted a retrospective cohort study of patients over age 18 undergoing MRI between May 2005 and October 2010 at Tufts Medical Center (TMC) with follow-up through November 2013. The electronic medical record was queried to determine imaging site, reason for scan, evaluation following radiology report, and final diagnosis. Results. 49,678 MRIs were done with 110 patients meeting inclusion criteria. Twenty two percent underwent some evaluation, most commonly a complete blood count, serum protein electrophoresis, or bone scan. With median follow-up of 41 months, 6% of patients were diagnosed with malignancies including multiple myeloma, non-Hodgkins lymphoma, metastatic non-small cell lung cancer, and metastatic adenocarcinoma. One patient who had not undergone evaluation developed breast cancer 24 months after the MRI. Conclusions. Incidentally noted abnormal or heterogeneous bone marrow signal on MRI was not inconsequential and should prompt further evaluation.

Subsequent primary malignancies after diffuse large B-cell lymphoma in the modern treatment era

With the addition of rituximab and other treatment advances, survival after diffuse large B‐cell lymphoma (DLBCL) has improved, but subsequent primary malignancies (SPMs) have emerged as an important challenge for DLBCL survivorship. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23 879 patients who survived at least 1 year after a first primary DLBCL diagnosed during 1989–2012, compared to the general population in California. Cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. We found that the incidence of acute myeloid leukaemia (AML) nearly doubled in the post‐rituximab era [SIR (95% CI) 4·39 (2·51–7·13) pre‐ (1989–2000) and 8·70 (6·62–11·22) post‐rituximab (2001–2012)]. Subsequent thyroid cancer was rare pre‐rituximab, but increased substantially after 2001 [0·66 (0·08–2·37) vs. 2·27(1·44–3·41)]. The 5‐year CMI for all SPMs (4·77% pre‐ vs. 5·41% post‐rituximab, P = 0·047), AML (0·15% vs. 0·41%, P = 0·003), thyroid cancer (0·03% vs. 0·15%, P = 0·003) and melanoma (0·25% vs. 0·42%, P = 0·020) were greater in DLBCL patients diagnosed in the post‐ versus pre‐rituximab period. This study provides insight into the changing pattern of SPM occurrence after the introduction of rituximab, which may elucidate the aetiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients.

Association Between Autologous Stem Cell Transplant and Survival Among Californians With Multiple Myeloma.

Background Autologous hematopoietic stem cell transplant (aHSCT) is an efficacious treatment for newly diagnosed multiple myeloma patients. However, as rapid advances have resulted in other highly efficacious and less intensive therapies, the role of aHSCT has been questioned. Methods We utilized population-based data to identify 13 494 newly diagnosed patients younger than age 80 years between 1998 and 2012. Patient characteristics of aHSCT and non-aHSCT groups were balanced using inverse probability weighting of a propensity score predicting aHSCT use. Multivariable models adjusted for baseline comorbidities, demographics, and socioeconomic status estimated the adjusted hazard ratio (aHR) and 95% confidence intervals (CIs) of death. Results Twenty point eight percent (2807) of patients underwent aHSCT, and this rate increased over time from 15.4% in 1998-2002 to 23.9% in 2008-2012. aHSCT was utilized among 37.6% and 11.5% of patients younger than age 60 years and 60 to 79 years, respectively. The median time to aHSCT was 9.4 months, and 89% of all aHSCTs occurred within two years of diagnosis. The median overall survival from time of aHSCT was 72.9 months (95% confidence interval [CI] = 68 to 78). Autologous HSCT at any time was associated with improved survival (aHR = 0.83, 95% CI = 0.75 to 0.92). Among aHSCT recipients, transplant more than 12 months after diagnosis (vs ≤12 months) was associated with worse survival (aHR = 1.33, 95% CI = 1.16 to 1.51). The positive effect of aHSCT on overall survival was similar across study time periods and age groups. Conclusion In the era of highly efficacious induction therapies, aHSCT remained infrequently used but continued to be associated with improved survival for multiple myeloma patients and should be considered for newly diagnosed patients.