Allison Rosenthal

Carfilzomib and the cardiorenal system in myeloma: An endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Janus kinase inhibitors for the treatment of myeloproliferative neoplasms

Introduction: Disordered signaling through the JAK/STAT pathway is a hallmark of myeloproliferative neoplasms (MPNs). Targeted therapies that inhibit and regulate this pathway are reasonable strategies for disease management. Only one JAK1/JAK2 inhibitor has gained FDA approval for treatment of myelofibrosis. Despite significant reductions in splenomegaly and disease-associated symptoms, additional agents are necessary to manage disease in those that do not respond. Areas covered: A review of the currently available literature and meeting abstracts for JAK inhibitors in myeloproliferative neoplasms identified studies aimed at improving outcomes and establishing alternative therapies in MPNs. Development of specific JAK inhibitors and ongoing trials involving ruxolitinib, CYT387, SAR302503, CEP701, SB 1518, XL-019, LY2784544, BMS-911453, NS-018, AZD1480 and INCB039110 are reviewed. Expert opinion: The identification of JAK2V617F mutation and its link to MPNs has revolutionized treatment options. Resultant research in targeting the JAK/STAT pathway led to the approval of ruxolitinib, a JAK1/JAK2 inhibitor with activity in MPNs. While ruxolitinib produces durable reductions in splenomegaly and improvement of symptoms, and prolongs survival, there is room for new and more specific agents to be developed. Minimizing toxicity and avoiding drug resistance are challenges that lie ahead. Combining agents with different mechanisms seems to be a rational strategy.

High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: Double hit and triple hit lymphomas and double expressing lymphoma.

Diffuse large B-cell lymphomas with aberrations in MYC, BCL2 and/or BCL6 by genetic alterations or protein expression represent a group of high grade B-cell lymphomas with inferior outcomes when treated with standard RCHOP chemotherapy. As a result, intensified induction regimens have been suggested in an effort to improve outcomes. Conclusions to date have largely been drawn from retrospective data although prospective data is slowly starting to emerge. Chemoimmunotherapy refractoriness is problematic and relapse rates are high. Patients with double hit lymphoma appear to have increased risk of CNS involvement and prophylaxis is recommended. There is insufficient evidence available to date to strongly recommend for or against consolidative stem cell transplant in this population. Collaborative clinical trials will be needed to establish a preferred therapeutic regimen and an appropriate standard of care in this unique group of patients with DLBCL.

A Phase Ib Study of the combination of the Aurora Kinase Inhibitor Alisertib (MLN8237) and Bortezomib in Relapsed Multiple Myeloma

The proteasome inhibitor bortezomib is cornerstone of modern therapy for multiple myeloma (MM). When used in combination therapy at diagnosis, response rates are 80–90%, but as a single agent, in relapse, response rates are only 30– 40%. To better understand the molecular basis for response and resistance, we performed druggable genome-wide RNA interference studies (siRNA) to identify genes that, when suppressed, would synergistically enhance or abrogate the cytotoxicity of proteasome inhibition (Zhu et al, 2011; Tiedemann et al, 2012). AURKA (aurora kinase A) and AURKB (aurora kinase B) were identified as lethal targets in MM while suppression of these genes also sensitized MM cells to bortezomib. Alisertib (MLN8237) is an oral small molecule inhibitor of aurora kinase A (Carvajal et al, 2006). The safety and bioactivity of alisertib has been studied in several Phase I trials and has been generally well tolerated in patients with solid tumours (Cervantes et al, 2012; Dees et al, 2012; Falchook et al, 2014). With doses under 100 mg, the doselimiting toxicities have been largely mechanistic (haematological toxicities and mucositis) and manageable (Kelly et al, 2014). With supportive pre-clinical work, we conducted a Phase I open-label multicentre clinical trial testing the combination of alisertib and bortezomib. No corticosteroids were used. Patients who were aged ≥18 years with relapsed MM, measurable disease, good performance status and laboratory results demonstrating adequate blood, kidney and liver profiles were eligible. All patients provided written informed consent. Enrolment began on 5 February 2010 and expansion opened on 15 June 2012. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice and was approved by the relevant Regulatory and Institutional Review Boards. A standard ‘3 + 3’ design for dose escalation was utilized in Phase I. Alisertib initial dose level O was 25 mg PO daily and bortezomib was 1 3 mg/m IV on days 1, 4, 8, and 11 on a 28-day cycle. Data from concurrent Phase I trials prompted an addendum. Subsequently, alisertib was given twice daily at escalating doses from 20 mg to 50 mg PO BID days 1–7 on a 28-day cycle and bortezomib dosing was changed to the more convenient schedule of 1 5 mg/m weekly continuously. Amended dose level 0 was alisertib 20 mg PO BID with bortezomib 1 5 mg/m IV. Alisertib dosing was escalated from 20 mg to 50 mg PO BID in successive cohorts to determine the maximum tolerated dose (MTD) [level 0: 25 mg PO daily – 3 patients, amended level 0: 20 mg PO BID3 patients plus 1 (dosing error), level 1: 30 mg PO BID – 3 patients, level 2: 40 mg PO BID -3 patients, and level 3: 50 mg PO BID – 6 patients]. Patients were observed until the end of cycle 2 and assessed for toxicity. No dose limiting toxicities (DLT) were documented, although one patient (level 3 dose) did require platelet transfusion to proceed to cycle 2 on schedule. Doses were not further escalated as information from on-going trials indicated additional escalation would be associated with increased toxicity. If a patient failed to complete the initial cycle of therapy for reasons other than toxicity, the patient was regarded as treatment intolerant and was taken off study. All toxicity information was utilized in the analysis. The final cohort was expanded with an additional 7 patients receiving treatment. The initial planned maximum number of treatment cycles was 10, although responding patients were considered for additional cycles. Treatment was continued until progression, unacceptable toxicity, patient refusal, new primary malignancy or other medical problems. The primary endpoint was defining a MTD and describing toxicities of the combination of alisertib and bortezomib. The final dose cohort was expanded to evaluate overall response rate (ORR). All patients that received at least one dose of study drug were assessed for safety and response. Adverse events were monitored using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_ 2010-06-14_QuickReference_8.5x11.pdf). Response was evaluated using the uniform response criteria established by the International Myeloma Working Group (Durie et al, 2006). Nineteen patients were treated during Phase I, with an additional 7 patients included in an expansion cohort (total 26 patients). Baseline characteristics are shown in Table SI. 14/26 (53 9%) patients were relapsed while 12 (46 1%) were relapsed and refractory. 96 2% (25/26) of patients had previous exposure to immunomodulatory drugs (IMiDs) and none were bortezomib-refractory. Median follow-up was 20 6 months (range 4 3–36 6). At last follow-up, 22 patients had progressed, while four had not. 12 patients were still alive and 14 had died. No patients Correspondence

A phase 2 study of lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) for untreated low-grade non-Hodgkin lymphoma requiring therapy

Patients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m2 day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m2 days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenströms macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.

Small Molecule Inhibitors in Chronic Lymphocytic Lymphoma and B Cell Non-Hodgkin Lymphoma.

Purpose of ReviewThe purpose of this review is to summarize the available literature for the use of small molecule inhibitors in chronic lymphocytic leukemia and B cell non-Hodgkin lymphoma.Recent FindingsIbrutinib, idelalisib, and venetoclax are small molecule inhibitors that have revolutionized therapeutic options for patients with CLL, particularly for those with high-risk disease including 17p deletion. These drugs are increasingly finding application in a variety of subtypes of B cell NHL. Intolerance and resistance are concerns for select patients, highlighting the need for continual development of alternate therapies.SummaryThe treatment armamentarium for CLL and NHL is vastly different than it was just a few years ago. Patients have a much wider range of non-chemotherapy treatment options, some of which produce durable responses and have long-term tolerability. Future research directions will likely focus on identifying the optimal sequences and combination strategies for these new targeted therapies.

Extramedullary Cardiac Multiple Myeloma—A Case Report and Contemporary Review of the Literature

Multiple myeloma (MM) is characterized by a clonal proliferation of plasma cells. Although the bone marrow is the usual site of involvement, extramedullary plasmacytomas (EMPs) also occur, affecting any tissue. Cardiac and pericardial involvement, although described, have been rare occurrences. We present the case of a 61-year-old female patient 47 days after autologous stem cell transplant for MM who developed cardiac tamponade owing to extramedullary recurrence of myeloma, pulmonary embolism, and takotsubo cardiomyopathy. We performed a review of the published studies of all cases of MM presenting at diagnosis or relapse with cardiac or pericardial involvement in the past 25 years. Including our patient, 34 patients with plasmacytoma involving cardiac or pericardial structures were identified from the literature search. Approximately equal numbers of patients were male and female (42% and 57%, respectively). The mean age was 62 years. Primary plasmacytomas accounted for 12% of the cases. A history of MM, EMP, or monoclonal gammopathy of uncertain significance was noted in two thirds of the cases (66.6%). Treatment included chemotherapy and/or high-dose corticosteroids in 81.1% of cases and 27% underwent radiation therapy. The reporting of all cases to date has focused on unusual findings, rather than treatment approaches or new therapeutic strategies that might benefit patients. We suggest the formation of a database of all cases of cardiac and pericardial EMPs, with a focus on predictive disease variables, standardized staging, outcomes, and survival, to ensure that patients are optimally treated in the modern era.

Unicentric castleman disease complicated by paraneoplastic bronchiolitis obliterans and pemphigus

Bronchiolitis obliterans (BO) and paraneoplastic pemphigus are rare and ominous complications of Castleman disease. Collectively, these processes have been reported as part of paraneoplastic autoimmune multiorgan syndrome (PAMS), and they can occur in the setting of various hematologic malignant tumors, carcinoid tumors, and melanoma. Irrespective of the underlying malignancy driving PAMS, the clinical outcomes are uniformly poor, and there are no standard treatment regimens, given the clinical rarity of the syndrome. We describe 2 patients with unicentric Castleman disease complicated by paraneoplastic pemphigus and bronchiolitis obliterans. In addition to primary surgical resection for Castleman disease, we also used therapy from a treatment protocol used for bronchiolitis obliterans resulting from hematopoietic stem cell transplant (HSCT). We were able to treat the patients using intravenous immunoglobulin; rituximab; fluticasone, azithromycin, and montelukast (FAM); and rosuvastatin therapy. One patient demonstrated a favorable response, while the other demonstrated minimal response to this therapy.

A phase 2 study of rituximab, cyclophosphamide, bortezomib and dexamethasone (R-CyBorD) in relapsed low grade and mantle cell lymphoma

Abstract In this phase 2 trial, we sought to evaluate the efficacy and safety of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD) in patients with low-grade NHL. The regimen included rituximab on day 1 with weekly cyclophosphamide, dexamethasone, and bortezomib 1.3 mg/m2 IV in a 28-day cycle. Twenty one patients were enrolled on the study. Median age was 69 years (range 51–80) and 17 (81%) patients had two or more prior treatments. Histologies included FL (n = 8), MCL (n = 8), and LPL/WM (n = 5). Hematologic toxicity and peripheral sensory neuropathy were the most common adverse events. With a median follow-up of 38.1 months, ORR was 13/21 (62%), with 4 (19%) CR. The ORR was 7/8 (88%) in FL and was 4/5 (80%) in LPL/WM. Median PFS and OS were 11.6 months and 54.8 months, respectively. R-CyBorD is an effective regimen in relapsed FL and LPL/WM patients with an acceptable safety profile.

Pitfall of 18F-FDG PET/CT in Characterization of Relapsed Multisystem Lymphomatoid Granulomatosis

We present serial 18F-FDG PET/CT findings in a case of grade 3 pulmonary lymphomatoid granulomatosis positive for the Epstein–Barr virus. The patient experienced a transient complete response to R-CHOP chemotherapy and subsequent multisystem recurrence, predominately involving the subcutaneous region of the torso on 18F-FDG PET/CT. Biopsy of the most hypermetabolic subcutaneous lesion demonstrated grade 1 cutaneous lymphomatoid granulomatosis negative for the Epstein–Barr virus. This report highlights the role of 18F-FDG PET/CT in characterizing and monitoring disease progression and regression, as well as the limitations of 18F-FDG PET/CT in accurate grading of multisystem recurrence, given the diversity of clinical and histopathologic features of lymphomatoid granulomatosis.