Terri L. Parker

Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Toxic erythema of chemotherapy following i.v. BU plus fludarabine for allogeneic PBSC transplant.

I.v. BU plus fludarabine is an effective conditioning regimen for myeloid neoplasias with low treatment-related mortality. At standard doses, cutaneous toxicity has been reported in <5% of cases. As we observed a much higher incidence of cutaneous toxicity in patients who received predominantly pharmacokinetically based doses of BU, we performed a retrospective analysis of 61 patients who received i.v. BU plus fludarabine (+/− antithymocyte globulin; ATG) as a conditioning regimen before allogeneic PBSC transplant. Of the 58 evaluable patients, 33 (57%) developed cutaneous toxicity that fell within the spectrum of toxic erythema of chemotherapy (TEC). The median onset of TEC was 22 days and most patients had multiple sites of involvement, with the groin, axillae and palms/soles being the favored sites. In men, scrotal involvement, sometimes severe, was also commonly observed. Initially, allergic reactions to antibiotics, fungal infections and GVHD were also considered until the clinical presentation of TEC became well recognized. In all patients, the skin healed without specific therapy but resolution often required several weeks. This series suggests that TEC is common after BU/fludarabine+/− ATG and it is important for transplant physicians to recognize, particularly as misdiagnosis could lead to inappropriate treatment.

Leukaemic vasculitis with myelodysplastic syndrome

www.thelancet.com Vol 386 August 1, 2015 501 A 75-year-old black woman with insulin-dependent diabetes and obesity presented in January, 2015, with a 10 day history of pruritic lesions on her arms and legs, 2–3 months of night sweats, and 3 weeks of right-sided headache, sinus pain, and congestion. The skin lesions had developed while she was taking prednisone for presumed temporal arteritis. She had no associated fever, abdominal pain, diarrhoea, myalgia, or arthralgia. On examination she looked well. On the extensor elbows extending down her forearms bilaterally and on her knees and shins were dozens of 1–2 cm oedematous pink-red papules with a darker red-violet central zone, resembling atypical papular target lesions of erythema multiforme (fi gure). She had similar lesions on the knees and shins. Along Wallace’s lines on the medial aspect of her feet and the tips of her fi ngers and toes were about 20 red macules, 5–15 mm in diameter. She had one 2 mm erosion on the soft palate of her mouth; her face was otherwise spared. Our diff erential diagnosis was erythema multiforme, erythema elevatum diutinum (a small vessel vasculitis that occurs on the extensor surfaces of joints on the arms and legs), and Sweet’s syndrome. Initial blood tests showed pancytopenia with white blood cell count 2·7 × 109/L with 43% neutrophils, 37% lymphocytes, 8% monocytes, 1% eosinophils, 1% atypical lymphocytes, and 10% bands; haemoglobin 100 g/L and platelet count 129 × 109/L; and mild neutropenia with absolute neutrophil count 1·4 × 109/L. Liver function tests were normal; urinalysis showed 2+ protein and no blood. PCR for herpes simplex virus, antineutrophil cytoplasmic antibody, and cryoglobulins were negative, antinuclear antibody was less than 1:40, there were no discrete abnormal bands in serum or urine protein electrophoresis, and no evidence of a monoclonal component on immunofi xation electrophoresis. However, quantitative immunoglobulins showed IgA about twice the upper limit of normal (8860 mg/L, normal 700–4000 mg/L). Two skin biopsy specimens showed an infi ltrate of atypical mononuclear cells around and within small and medium-sized vessels with associated vascular damage (extravasated erythrocytes, leucocytoclasia, and fi brinoid degeneration). The atypical cells had blastic morphological features and were variably positive for myeloperoxidase, CD15, CD43, CD45, CD68, and TIA-1. The epidermis had scattered necrotic keratinocytes. Direct immunofl uorescence did not show any specifi c deposits of IgG, IgM, IgA, or complement. Histopathology fi ndings were consistent with leukaemic vasculitis mediated by atypical myeloid cells. Bone marrow biopsy specimen showed increased early myeloid forms with 5% CD34+ myeloblasts with abnormal localisation of immature precursors and dysme gakaryopoiesis in normocellular marrow without fi brosis. 11/18 bone marrow cells in metaphase showed an abnormal clone with a complex karyotype with an extra copy of chromosome 1, deletions in 1q, 3p, and 5q, and losses of one copy of chromosomes 7, 17, and 22 (45,XX,+1,del(1)(q21),del(3)(p14),del(5)(q13q31),-7,-17, -22[cp11]/46,XX[7]). FISH showed deletions of 5q and 7q in about 54% of bone marrow cells. These fi ndings were diagnostic of myelodysplastic syndrome (MDS) with refractory anaemia with excess blasts-1. By contrast with leucocytoclastic vasculitis, which is more commonly associated with MDS and is mediated by mature-appearing neutrophils, in rare circumstances leukaemic cells mediate blood vessel damage directly, causing leukaemic vasculitis. As in our case, the skin lesions are typically erythematous or purpuric papules, nodules, or plaques distributed on the limbs, which can mimic erythema multiforme. Leukaemic vasculitis is unusual as the presenting feature of MDS, because it is usually associated with acute myeloid leukaemia or myelodysplastic syndrome in transformation. On the basis of her RAEB-1 WHO category, complex karyotype, and no transfusion requirement, our patient’s WHO classifi cation-based Prognostic Scoring System Score at diagnosis was 4, placing her in the high-risk category with an expected median survival of 26 months. The presence of leukaemic vasculitis also portends a poor prognosis. Because she had not responded to corticosteroids we gave azacitidine 75 mg/m2 subcutaneously for 7 days, with great improvement in her white cell count and skin lesions (appendix), followed by three additional cycles of monthly azacitidine. At last follow-up in June, 2015, 4 months after her fi rst dose of azacitidine she remains well and has an excellent ongoing haematological response except for mild anaemia. Her skin lesions healed well leaving only postinfl ammatory pigmentation. She has not needed transfusion of any blood products since she started azacitidine treatment. Leukaemic vasculitis with myelodysplastic syndrome

Whole-exome sequencing in evaluation of patients with venous thromboembolism

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various SERPIN genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had >1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.

Antigen-mediated regulation in monoclonal gammopathies and myeloma

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial

Micro‐Abstract The goal of the present study was to evaluate a novel prospective influenza vaccination strategy for patients with plasma cell disorders. Fifty‐one patients were treated with a 2‐dose series of high‐dose inactivated trivalent influenza vaccine. This vaccination strategy was well tolerated and led to very high rates of seroprotection against influenza. Background: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. Patients and Methods: Patients with plasma cell dyscrasia (n = 51) were treated with a 2‐dose series of high‐dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory‐confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. Results: Influenza vaccine was well tolerated, without any vaccine‐related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory‐confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09‐like virus; A/Texas/50/2012 [H3N2]‐like virus; and a B/Massachusetts/2/2012‐like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. Conclusion: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high‐dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.

Stem-Cell Transplantation for Amyloidosis: Improving Outcomes but Not for the Faint of Heart

Immunoglobulin (Ig) light-chain amyloidosis (AL) is a multisystem disorder characterized by the deposition of misfolded immunoglobulin light chains as amyloid fibrils, leading to organ dysfunction. Prognosis of patients with AL amyloidosis is greatly impacted by the degree and pattern of organ involvement, with cardiac involvement as the key determinant of outcome. Therapy of AL amyloidosis has been largely directed toward the often indolent plasma cell clone responsible for the production of amyloidogenic Ig and inspired by advances in the therapy of multiple myeloma (MM). High-dose melphalan (HDM) with autologous stem-cell transplantation (ASCT) was introduced for the therapy of AL amyloidosis nearly 20 years ago. An attractive aspect of HDM/ASCT is the rapid reduction in amyloidogenic Ig and the depth of hematologic responses, which correlates with improvement in organ function. However, HDM/ASCT is also associated with higher rates of early transplantation-related mortality (TRM; ranging from 13% to 43%) in AL compared with the experience with this approach in MM. Nonetheless, several studies documented the feasibility of durable hematologic and organ responses and improved survival in patients treated with this approach. Another strategy that led to clinical responses was therapy with dexamethasone, initially alone, but soon combined with alkylating agents such as cyclophosphamide or melphalan. These data set the stage for a randomized clinical trial comparing HDM versus melphalan and dexamethasone (MelDex) in patients with AL amyloidosis. This trial failed to show superiority of HDM/ASCT over MelDex, but the interpretation was complicated by high rates of treatmentrelated early mortality (24%) observed in the ASCT arm. These data also dampened the enthusiasm for the use of ASCT in AL amyloidosis in recent years, particularly in Great Britain. Several hypotheses, including the role of patient selection, single-center versus multicenter nature, experience of the transplantation centers, and details of peritransplantation care, have been invoked to help understand the variance in TRM between different studies. Of these, the most objective data exist as to the importance of patient selection. Given the importance of cardiac involvement, it is not surprising that biomarkers of cardiac injury/dysfunction, such as cardiac troponin T and brain natriuretic peptide (BNP) or N-terminal pro-BNP, are important in predicting outcome and form the basis of current staging in AL amyloidosis. Although these staging systems are not optimal for selecting patients for ASCT, excluding patients with elevated cardiac biomarkers (eg, cardiac troponin T 0.06 ng/mL and N-terminal pro-BNP 5,000 ng/L) has permitted transplantation centers to reduce TRM to single-digit estimates, while permitting selected patients with cardiac AL to potentially benefit from this procedure. Whether application of such patient selection criteria will allow similarly low rates of TRM in the context of prospective multicenter studies of ASCT in AL amyloidosis remains to be demonstrated. Consideration of ASCT-based therapy for AL amyloidosis has been further complicated in recent years by the introduction of combination therapies with novel agents, particularly those using bortezomib. In single-arm studies, these regimens have been shown to mediate rapid reduction in light chains and high rates of hematologic response, with resultant improvement in organ function. Bortezomib-based regimens may also lead to improved organ function in patients who otherwise would not be candidates for ASCT at initial diagnosis because of the degree of organ dysfunction. Although the superiority of bortezomib-based therapies over MelDex has not yet been established in the context of a randomized trial, the rapid kinetics of hematologic response with these regimens raises questions about whether ASCT should be the preferred initial therapy even in ASCT-eligible patients. The ability to design larger multicenter studies with ASCT in AL amyloidosis depends on the feasibility of carrying out these studies with acceptable transplantation-related early mortality (EM). The study by D’Souza et al provides an important step in this direction. The authors analyzed data from the Center for International Blood and Marrow Transplantation Research database from 134 centers over three 5-year time cohorts between 1995 and 2012. The data demonstrate that in this real-world experience, impressive reductions in transplantation-related EM have been obtained over the past decade, and in the most recent cohort, the day 100 mortality rate of 5% is comparable to that achieved at larger centers. These data should provide reassurance when designing randomized studies comparing ASCT. Unfortunately, the lack of data about cardiac biomarkers, even in the most recent cohort, makes it difficult to evaluate the possible reasons behind the observed improvement in outcome and the contribution of better patient selection (v other possibilities) to the observed results. Centers that performed more AL transplantations a year (using a somewhat arbitrary cutoff of four or more transplantations per year) had a lower EM rate compared with centers that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 32 NOVEMBER 1

Pralatrexate: treatment of T-cell non-Hodgkin's lymphoma

Pralatrexate is a folate analogue metabolic inhibitor manufactured by Allos Therapeutics, Inc., a wholly-owned subsidiary of Spectrum Pharmaceuticals, Inc. In both preclinical and clinical studies, pralatrexate demonstrated activity in lymphoma. Pralatrexate was US FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma in 2009. Approval was based on data from the PROPEL trial that demonstrated an overall response rate of 29% in a heavily pretreated patient population. The dose and schedule of pralatrexate is 30-mg/m(2) weekly for 6 weeks, given in 7-week cycles. Folate and vitamin B12 supplementation are required to minimize toxicity. The most common toxicities are mucositis, thrombocytopenia, nausea and fatigue.

A Phase I Dose‐Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low‐Grade or Intermediate‐Grade B‐Cell or T‐Cell Lymphoma

Abstract Lessons Learned. Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule. Responses were seen in patients with T‐cell lymphomas, including cutaneous T‐cell lymphoma, but not in patients with aggressive B‐cell lymphomas. Background. Clofarabine is a second‐generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia. These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies. In this phase I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low‐grade or intermediate‐grade, B‐cell or T‐cell lymphoma. Methods. The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of three. The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the overall response rate of clofarabine administered once a week for 3 weeks and repeated every 4 weeks. Eligible patients were over the age of 18, had a histologically confirmed low‐grade or intermediate‐grade B‐cell or T‐cell lymphoma, and must have previously been treated with one standard chemotherapy regimen, excluding single‐agent rituximab. The primary objectives included in statistical analyses were MTD, toxicity, and overall response rate (ORR). Four patients were enrolled in cohort 1 (clofarabine 10 mg/m2), four in cohort 2 (clofarabine 15 mg/m2), three in cohort 3 (clofarabine 20 mg/m2), two in cohort 4 (clofarabine 30 mg/m2), and one in cohort 5 (clofarabine 40 mg/m2) (Table 2). Results. MTD was not reached in the study. The most common toxicity observed was myelosuppression. A total of four (29%) patients experienced grade 3 leukopenia, with three (21%) patients experiencing grade 4 neutropenia. The myelosuppression was not considered to be a dose‐limiting toxicity, as it resolved within 7 days. Fourteen patients were enrolled: 10 patients with T‐cell non‐Hodgkin lymphoma (NHL) and 4 patients with B‐cell NHL (see Table 1). All 14 patients received at least one dose of clofarabine and were evaluable for response. One patient with cutaneous T‐cell lymphoma (CTCL) had a partial response; five (36%) had stable disease, and eight patients (57%) had no response. The one patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography scan was observed with a partial response of the skin. Conclusion. In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10–40 mg/m2. In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2. Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest‐dose cohort.