Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring.

PURPOSE: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. PATIENTS AND METHODS: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. RESULTS: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. CONCLUSIONS: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.

Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy.

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

Imaging for Staging and Response Assessment in Lymphoma.

Lymphoma comprises a heterogeneous group of diseases; remarkable advances have been made in diagnosis and treatment. Diagnostic imaging provides important information for staging and response assessment in patients with lymphoma. Over the years, staging systems have been refined, and dedicated criteria have been developed for evaluating response to therapy with both computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (PET)/CT. The most recent system proposed for staging and response assessment, known as the Lugano classification, applies to both Hodgkin and non-Hodgkin lymphoma. The use of standardized criteria for staging and response assessment is important for making accurate treatment decisions and for determining the direction of further research. This review provides an overview of the updated CT and PET response criteria to familiarize the radiologist with the most important and clinically relevant aspects of lymphoma imaging. It also provides a short clinical update on lymphoma and the associated spectrum of imaging findings.

Noncontrast perfusion single-photon emission CT/CT scanning: a new test for the expedited, high-accuracy diagnosis of acute pulmonary embolism.

BACKGROUND: Standard ventilation and perfusion (V˙/Q˙) scintigraphy uses planar images for the diagnosis of pulmonary embolism (PE). To evaluate whether tomographic imaging improves the diagnostic accuracy of the procedure, we compared noncontrast perfusion single-photon emission CT (Q˙-SPECT)/CT scans with planar V˙/Q˙scans in patients at high risk for PE. METHODS: Between 2006 and 2010, most patients referred for diagnosis of PE underwent both Q˙-SPECT/CT scan and planar V˙/Q˙scintigraphy. All scans were reviewed retrospectively by four observers; planar scans were read with modified Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II and Prospective Investigative Study of Pulmonary Embolism Diagnosis (PISA-PED) criteria. On Q˙-SPECT/CT scan, any wedge-shaped peripheral perfusion defect occupying > 50% of a segment without corresponding pulmonary parenchymal or pleural disease was considered to show PE. The final diagnosis was established with a composite reference standard that included ECG, ultrasound of lower-extremity veins, D-dimer levels, CT pulmonary angiography (when available), and clinical follow-up for at least 3 months. RESULTS: One hundred six patients with cancer and mean Wells score of 4.4 had sufficient follow-up; 22 patients were given a final diagnosis of PE, and 84 patients were given a final diagnosis of no PE. According to PIOPED II, 13 studies were graded as intermediate probability. Sensitivity and specificity for PE were 50% and 98%, respectively, based on PIOPED II criteria; 86% and 93%, respectively, based on PISA-PED criteria; and 91% and 94%, respectively, based on Q˙-SPECT/CT scan. Seventy-six patients had additional relevant findings on the CT image of the Q˙-SPECT/CT scan. CONCLUSIONS: Noncontrast Q˙-SPECT/CT imaging has a higher accuracy than planar V˙/Q˙imaging based on PIOPED II criteria in patients with cancer and a high risk for PE.

Shall we report cardiomegaly at routine computed tomography of the chest?

PURPOSE: To examine the accuracy of the cardiothoracic ratio (CTR) at routine computed tomography (CT) of the chest to diagnose cardiomegaly by using echocardiography (ECHO) as a criterion standard, and secondarily, to search for CT cardiac measurements correlating with left ventricular hypertrophy (LVH) at ECHO. MATERIALS AND METHODS: We searched 2 databases: cancer patients who had chest CT who also underwent routine ECHO by one experienced cardiologist, from January to March 2008. Consecutive patients were enrolled who had chest radiography (CXR) within 1 month and ECHO within 6 months of CT. Cardiothoracic ratio was defined as the transverse greatest cardiac diameter from outer to outer myocardium on axial images divided by the transverse greatest thoracic diameter from inner to inner chest wall on axial images, as measured by 2 board-certified radiologists. Left ventricular short diameter on CT was measured from inner to inner myocardium. Left ventricular hypertrophy at ECHO was defined using the standard American Society of Echocardiography criteria. Other data captured included cardiac and chemotherapy history, and secondary signs of heart failure. The Pearson correlation coefficient (r) and Wilcoxon rank sum tests and receiver operating characteristic (ROC) curves were used for statistical analysis. RESULTS: 101 patients, 52 men and 49 women, with a mean age of 58 years met the entry criteria. Cardiothoracic ratio at CXR and CT were highly correlated (r = 0.802) (P < 0.001). There was moderate ability of CT CTR to identify LVH (area under the receiver operating characteristic curve AUC = 0.70; 95% CI, 0.51-0.90). The CT left ventricular short diameter showed moderate correlation with the ECHO left ventricular internal diameter (r = 0.49) and left ventricular mass (r = 0.37). CONCLUSION: In patients with cancer undergoing routine ECHO, the cardiothoracic ratio at routine CT scans was highly correlated with that at CXR. Preliminary estimates in this small study indicate a low likelihood of LVH when the CTR is less than 0.49.

Fine needle aspiration cytology of palpable and nonpalpable lymph nodes to detect metastatic melanoma.

BACKGROUND: Fine needle aspiration cytology (FNAC) is usually used to evaluate palpable nodes in patients with melanoma. The goal of our study is to review the sensitivity and specificity of this technique when applied to palpable but also to nonpalpable nodes. METHODS: FNAC was performed during 1984-2007 in 1279 patients with suspicious lesions and/or lymph nodes. Indications for biopsy included increased size and/or palpability of nodes or abnormal ultrasound findings such as increased perfusion or focal lesions within the lymph nodes. The sensitivity, specificity, and positive and negative predictive values of FNACs guided by palpation or ultrasound were calculated for all patients and for subgroups of patients with palpable nodes or nonpalpable but sonomorphologically suspicious nodes. RESULTS: A total of 2446 FNACs were performed in 1279 melanoma patients, of which 2011 (82.2%) FNACs had clinically or histologically confirmed results. Increased size and/or palpability of nodes was observed in 376 (29.4%) of 1279 patients, and abnormal ultrasound findings occurred for 903 (70.6%), indicating that a biopsy was needed. FNACs guided by palpation had sensitivity, specificity, and positive and negative predictive values similar to that of FNACs guided by ultrasound (sensitivity = 98.4% vs 97.2%, specificity = 100% vs 99.8%, positive predictive value = 100% vs 99.9%, and negative predictive value = 95.2% vs 96.4%, for palpation-guided FNACs vs ultrasound-guided FNACs, respectively). Results did not differ between patients with the palpable nodes and patients with nonpalpable but sonomorphologically suspicious nodes. CONCLUSIONS: Ultrasound-guided FNAC of suspicious lymph nodes and lesions in melanoma patients has a high sensitivity and specificity, and FNAC should not be limited to palpable nodes. FNAC of normal-sized nodes and/or lymph nodes with abnormal ultrasound findings can be used to identify early metastatic disease.

Renal oncocytosis: imaging considerations.

Renal oncocytosis is a very rare entity. Although it has been described in pathology and surgery literature, the imaging findings of renal oncocytosis have not yet been described in the radiology literature. We present three cases of renal oncocytosis. The imaging features and clinical considerations are discussed.

Imaging of late complications from mantle field radiation in lymphoma patients.

Hodgkin lymphoma is one of the most curable cancers because of its sensitivity to both radiation and several chemotherapy agents. Radical radiotherapy alone provided curative therapy for patients who had Hodgkin lymphoma as early as six decades ago. Yet, the radiation field included normal organs, such as breast tissue, thyroid, and coronary arteries, which were at risk for long-term complications. Dedicated imaging approaches have been developed to evaluate late radiation effects on these structures.

Coronary artery disease after radiation therapy for Hodgkin's lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients.

OBJECTIVE: Long-term survivors of Hodgkin's lymphoma treated with radiation therapy have an increased incidence of coronary artery disease. The purpose of this study is to describe the coronary CT angiography findings and calcium scores of asymptomatic patients who had mediastinal irradiation for Hodgkin's lymphoma and to evaluate the impact of coronary CT angiography on patient management. MATERIALS AND METHODS: We evaluated nine consecutive patients, age range 35-60 years, who had been treated for Hodgkin's lymphoma by radiation therapy between the ages of 11 and 27 years. The total mediastinal dose ranged from 34 to 45 Gy. All patients were evaluated with 64-MDCT with calcium scoring followed by CT angiography of the coronary arteries. Imaging findings and clinical follow-up were analyzed. RESULTS: Eight of nine patients had coronary artery disease. CT showed long segments of diffuse disease; areas of stenosis from soft plaque; and calcification in the proximal right coronary, left anterior descending, and left circumflex arteries. Calcium scores were significantly higher than in other patients of this age group. Additional tests, including selective coronary angiography, were necessary in patients with diffuse disease with calcifications. CT evaluation led to bypass surgery and angioplasty in two patients. CONCLUSION: Coronary CT angiography and calcium scores are useful tools for evaluation of irradiation-related coronary artery disease. Complementary tests might be necessary in selected patients. Prospective larger studies are needed to better define the role of coronary CT angiography and calcium scores and to establish an algorithm for evaluation and treatment of these patients.

Hodgkin's and non-Hodgkin's lymphomas.

The diagnosis and management of lymphoma have undergone significant changes in the past 20 years. For example, new immunophenotypic and molecular methods have replaced traditional histology-based classification schemes for lymphoma. Fluorine-18-deoxyglucose (FDG) positron emission tomography (PET) has evolved into a potent staging tool and prognostic indicator in many kinds of lymphoma. The role of radiation therapy, especially in patients who have early-stage Hodgkin's disease, has changed substantially. The introduction of anti-CD 20 antibody therapy (Rituximab) has improved the treatment of B-cell lymphoma. These changes are linked with higher expectations for imaging, such as detection of more subtle lymphoma manifestations, evaluation of residual changes, and better assessment of early response. This article reviews clinical and radiologic features of both Hodgkin's disease and non-Hodgkin's lymphoma. It also describes the radiologic staging of lymphoma and the emerging role of FDG-PET for assessing lymphoma.

Ultrasound-guided fine needle aspiration cytology prior to sentinel lymph node biopsy in melanoma patients.

BACKGROUND: Sentinel lymph node biopsy (SLNB) allows early detection of metastases, thereby enabling early treatment in melanoma patients likely to benefit from adjuvant therapies. This prospective study analyzes the possible benefits of additional ultrasound (US) and fine needle aspiration cytology (FNAC) of sentinel nodes (SN) prior to SLNB. METHOD: Over a 2-year period 127 melanoma patients with 151 SN were scheduled for SLNB. All SN were initially identified with lymphoscintigraphy, then identified and evaluated by US and the cells aspirated for cytology (FNAC). US findings and FNAC results were compared to surgical findings. RESULTS: Of 127 patients, 114 had one SN each, 12 had two, and one had three. In vivo US achieved a sensitivity of 79% (95% CI: 62-91%) and a specificity of 72% (95% CI: 62-81%). FNAC showed a sensitivity of 59% (95% CI: 41-76%) and a specificity of 100% (95% CI: 95-100%). The combination of these two in vivo methods achieved an overall sensitivity of 82% (95% CI: 65-93%) and an overall specificity of 72% [95% CI: 62-81%]. CONCLUSION: Combined US and FNAC provides important information prior to SLNB in that both procedures identify metastases in the lymph nodes (sensitivity > 80%). Patients with positive FNAC may proceed directly to complete lymph node dissection (cLND) instead of having initial SLNB. Thus, combined US and FNAC may prevent unnecessary anesthesia and surgical management as well reduce costs. In our study 16% (19/121) fewer SLNB procedures were carried out, subsequently replaced by cLND. For patients with a negative combination of in vivo US and FNAC, SLNB remains the best diagnostic option.

Percutaneous transluminal laser angioplasty versus balloon dilation for treatment of popliteal artery occlusions.

PURPOSE: To compare the immediate results, complication rates, and long-term outcomes of percutaneous transluminal laser angioplasty (PTLA) versus balloon dilation alone in the treatment of popliteal artery occlusions. METHODS: In a prospective nonrandomized study conducted between December 1994 and June 2000, 215 symptomatic patients with unilateral popliteal occlusions were treated with either dilation alone (88 patients: 52 men; mean age 62 years, range 48-83) or PTLA (127 patients: 70 men; mean age 64 years, range 49-86) using a 308-nm excimer laser followed by dilation. The average occlusion length was 10.4 cm (range 3-14). RESULTS: PTLA was successful in recanalizing 105 (82.7%) arteries, while the recanalization rate for dilation alone was only 70.4% (62/88; p=0.045). After a mean follow-up of 36 months (range 6-52), the primary and secondary patency rates were 21.7% and 50.8%, respectively, in patients with PTLA and 16.3% and 35.2% in the angioplasty group (p=0.762). The complication rates associated with both techniques were similar. CONCLUSIONS: Although initial recanalization may be better with PTLA, it does not appear to add any long-term benefit over balloon dilation alone.