Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

Real-world experience with ponatinib therapy in chronic phase chronic myeloid leukemia: impact of depth of response on survival and prior exposure to nilotinib on arterial occlusive events.

We surveyed the performance of ponatinib, as salvage therapy, in a real-world setting of chronic phase chronic myeloid leukemia (CML-CP). Among 55 consecutive patients (median age 49 years) with relapsed/refractory CML-CP, 35 (64%) had failed ≥3 tyrosine kinase inhibitors (TKIs), 35 (64%) were pre-treated with nilotinib, and 14 (28%) harbored ABL1T315I. At start of ponatinib (median dose 30 mg/day), 40 patients were already in complete hematologic (CHR), 4 in complete cytogenetic (CCyR), 3 in major molecular (MMR) remission, while 8 had not achieved CHR (NR). Ponatinib improved the depth of response in 13 (33%), 3 (75%), 2 (66%), and 4 (50%) patients with CHR, CCyR, MMR, and NR, respectively (p = 0.02). At a median follow-up of 42 months, 13 (23%) deaths, 5 (9%) blast transformations, and 25 (45%) allogeneic transplants were recorded. Five/10-year post-ponatinib survival was 77%/58% with no significant difference when patients were stratified by allogeneic transplant (p = 0.94), ponatinib-induced deeper response (p = 0.28), or a post-ponatinib ≥CCyR vs CHR remission state (p = 0.25). ABL1T315I was detrimental to survival (p = 0.04) but did not appear to affect response. Prior exposure to nilotinib was associated with higher risk of arterial occlusive events (AOEs; 11% vs 0%; age-adjusted p = 0.04). Ponatinib starting/maintenance dose (45 vs 15 mg/day) did not influence either treatment response or AOEs. Our observations support the use of a lower starting/maintenance dose for ponatinib in relapsed/refractory CML-CP but a survival advantage for deeper responses was not apparent and treatment might not overcome the detrimental impact of ABL1T315I on survival. The association between prior exposure to nilotinib and a higher risk of post-ponatinib AOEs requires further validation.

Resolution of acute pulmonary embolism using anticoagulation therapy alone in coronavirus disease 2019.

OBJECTIVE: To investigate the radiographic resolution of acute pulmonary embolism (PE) using contrast-enhanced computed tomography (CECT) examinations in patients diagnosed with acute PE while hospitalized with coronavirus disease 2019 (COVID-19) and to understand the mid-term and long-term implications of anticoagulation therapy. METHODS: We identified patients with acute PE per CECT and at least one follow-up CECT from March 11, 2020, to May 27, 2021, using a prospective registry of all hospitalized patients with COVID-19 infection receiving care within a multicenter Health System. Initial and follow-up CECT examinations were reviewed independently by two radiologists to evaluate for PE resolution. The Modified Miller Score was used to assess for thrombus burden at diagnosis and on follow-up. RESULTS: Of the 6070 hospitalized patients with COVID-19 infection, 5.7% (348/6070) were diagnosed with acute PE and 13.5% (47/348) had a follow-up CECT examination. The mean ± standard deviation time to follow-up imaging was 44 ± 48 days (range, 3-161 days). Of 47 patients, 47 (72.3%) had radiographic resolution of PE, with a mean time to follow-up of 48 ± 43 days (range, 6-239 days). All patients received anticoagulation monotherapy for a mean of 149 ± 95 days and this included apixaban (63.8%), warfarin (12.8%), and rivaroxaban (8.5%), among others. The mean Modified Miller Score at PE diagnosis and follow-up was 4.8 ± 4.2 (range, 1-14) and 1.4 ± 3.3 (range, 0-16; P < .0001), respectively. Nine patients (19%) died at a mean of 13 ± 8 days after follow-up CECT (range, 1-27 days) and at a mean of 28 ± 16 days after admission (range, 11-68 days). Seen of the nine deaths (78%) deaths were associated with progression of COVID-19 pneumonia. CONCLUSIONS: Hospitalized patients with COVID-19 have a clinically apparent 5.7% rate of developing PE. In patients with follow-up imaging, 72.3% had radiographic thrombus resolution at a mean of 44 days while on anticoagulation. Prospective studies of the natural history of PEs with COVID-19 that include systematic follow-up imaging are warranted to help guide anticoagulation recommendations.

Hemophagocytic Lymphohistiocytosis for the Internist and Other Primary Care Providers.

Hemophagocytic lymphohistiocytosis (HLH) syndrome is a hyperinflammatory state that leads to life-threatening, disproportionate activation of the immune system and may be confused for and concomitantly exist with sepsis. However, its treatment differs from sepsis, requiring early initiation of immunosuppressive treatment. While HLH syndrome is more commonly diagnosed in children, internists and other primary care providers must be familiar with the diagnosis and treatment of adult patients with HLH in the hospital and outpatient setting. In this article, we review the essentials that an internist and other primary care providers managing adult HLH patients should know.

Deep vein thrombosis in the setting of Klippel-Trenaunay syndrome and sirolimus treatment.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular disorder characterized by the triad of cutaneous capillary malformation, lymphatic and venous anomalies, and soft tissue and bone overgrowth. Sirolimus is a mechanistic target of rapamycin inhibitor used as an immunosuppressive drug. It has also been used to improve and treat vascular malformations that can predispose to intravascular coagulopathy. We have described the case of a patient with KTS receiving a therapeutic anticoagulation dose, for whom sirolimus was initiated, and who had presented with an extensive venous thromboembolism. Correlations between the use of sirolimus in patients with KTS are limited, and cautious use and monitoring could be necessary.

Deep vein thrombosis and pulmonary embolism among hospitalized coronavirus disease 2019-positive patients predicted for higher mortality and prolonged intensive care unit and hospital stays in a multisite healthcare system.

OBJECTIVE: We assessed the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients with coronavirus disease 2019 (COVID-19) compared with that in a matched cohort with similar cardiovascular risk factors and the effects of DVT and PE on the hospital course. METHODS: We performed a retrospective review of prospectively collected data from COVID-19 patients who had been hospitalized from March 11, 2020 to September 4, 2020. The patients were randomly matched in a 1:1 ratio by age, sex, hospital of admission, smoking history, diabetes mellitus, and coronary artery disease with a cohort of patients without COVID-19. The primary end point was the incidence of DVT/PE and the odds of developing DVT/PE using a conditional logistic regression model. The secondary end point was the hospitalization outcomes for COVID-19 patients with and without DVT/PE, including mortality, intensive care unit (ICU) admission, ICU stay, and length of hospitalization (LOH). Multivariable regression analysis was performed to identify the variables associated with mortality, ICU admission, discharge disposition, ICU duration, and LOH. RESULTS: A total of 13,310 patients had tested positive for COVID-19, 915 of whom (6.9%) had been hospitalized across our multisite health care system. The mean age of the hospitalized patients was 60.8 ± 17.0 years, and 396 (43.3%) were women. Of the 915 patients, 82 (9.0%) had had a diagnosis of DVT/PE confirmed by ultrasound examination of the extremities and/or computed tomography angiography of the chest. The odds of presenting with DVT/PE in the setting of COVID-19 infection was greater than that without COVID-19 infection (0.6% [5 of 915] vs 9.0% [82 of 915]; odds ratio [OR], 18; 95% confidence interval [CI], 8.0-51.2; P < .001). The vascular risk factors were not different between the COVID-19 patients with and without DVT/PE. Mortality (P = .02), the need for ICU stay (P < .001), duration of ICU stay (P < .001), and LOH (P < .001) were greater in the DVT/PE cohort than in the cohort without DVT/PE. On multivariable logistic regression analysis, the hemoglobin (OR, 0.71; 95% CI, 0.46-0.95; P = .04) and D-dimer (OR, 1.0; 95% CI, 0.33-1.56; P = .03) levels were associated with higher mortality. Higher activated partial thromboplastin times (OR, 1.1; 95% CI, 1.00-1.12; P = .03) and higher interleukin-6 (IL-6) levels (OR, 1.0; 95% CI, 1.01-1.07; P = .05) were associated with a greater risk of ICU admission. IL-6 (OR, 1.0; 95% CI, 1.00-1.02; P = .05) was associated with a greater risk of rehabilitation placement after discharge. On multivariable gamma regression analysis, hemoglobin (coefficient, -3.0; 95% CI, 0.03-0.08; P = .005) was associated with a prolonged ICU stay, and the activated partial thromboplastin time (coefficient, 2.0; 95% CI, 0.003-0.006; P = .05), international normalized ratio (coefficient, -3.2; 95% CI, 0.06-0.19; P = .002) and IL-6 (coefficient, 2.4; 95% CI, 0.0011-0.0027; P = .02) were associated with a prolonged LOH. CONCLUSIONS: A significantly greater incidence of DVT/PE occurred in hospitalized COVID-19-positive patients compared with a non-COVID-19 cohort matched for cardiovascular risk factors. Patients affected by DVT/PE were more likely to experience greater mortality, to require ICU admission, and experience prolonged ICU stays and LOH compared with COVID-19-positive patients without DVT/PE. Advancements in DVT/PE prevention are needed for patients hospitalized for COVID-19 infection.

ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Clinical outcomes of adults with hemophagocytic lymphohistiocytosis treated with the HLH-04 protocol: a retrospective analysis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy (n = 9), autoimmune (n = 8), infection (n = 8), and idiopathic (n = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29, p = 0.003), platelets <100 × 109/L (HR 4.06, p = 0.027), ANC <1 × 109/L (HR 5.24, p = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30, p = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.

Diagnosis and Management of Genetic Iron Overload Disorders.

Iron overload disorders lead to excess iron deposition in the body, which can occur as a result of genetic or secondary causes. Genetic iron overload, referred to as hereditary hemochromatosis, may present as a common autosomal recessive mutation or as one of several uncommon mutations. Secondary iron overload may result from frequent blood transfusions, exogenous iron intake, or certain hematological diseases such as dyserythropoietic syndrome or chronic hemolytic anemia. Iron overload may be asymptomatic, or may present with significant diseases of the liver, heart, endocrine glands, joints, or other organs. If treated appropriately prior to end-organ damage, life expectancy has been shown to be similar compared to matched populations. Alongside clinical assessment, diagnostic studies involve blood tests, imaging, and in some cases liver biopsy. The mainstay of therapy is periodic phlebotomy, although oral chelation is an option for selected patients.

Pharmacokinetics-based clinical management of acquired von Willebrand syndrome: a case report.

von Willebrand disease (VWD) is a common bleeding disorder caused by defective or low levels of von Willebrand factor (VWF). Although most cases of VWD are caused by genetic mutations, some are acquired due to various disease states. In managing VWD, the aim is to normalize plasma levels of both VWF and factor VIII (FVIII), as this aids in hemostasis. Desmopressin usually corrects VWF level in type 1 VWD by inducing the release of endogenous VWF. In cases where desmopressin is ineffective or cannot be used, transfusion of virally inactivated, plasma-derived VWF/FVIII concentrate or infusion of recombinant VWF (Vonvendi) is indicated. Treatment of acquired von Willebrand syndrome (AVWS) aims to control the underlying disease while regulating life-threatening hemorrhages with infusions of VWF/FVIII concentrate. Wide intrasubject variability in VWF and FVIII levels, particularly in AVWS, necessitates verification of response to treatment by frequent monitoring of the plasmatic VWF level. Clinical pharmacokinetics of VWF may facilitate calculation of the necessary loading and maintenance doses of VWF/FVIII concentrate in the management of AVWS patients undergoing surgery, thereby avoiding unnecessary infusion of coagulation factor concentrate.

A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis.

Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058).

Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib.

Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach to obtain maximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining 2 different doses of ixazomib (4 mg and 5.5 mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma. Seventy patients were enrolled, 35 patients randomly assigned to each ixazomib dose. Overall, 30 (43%; 95% confidence interval, 31-55) of the patients achieved a confirmed partial response or better, with 31% achieving a response with 4 mg and 54% with 5.5 mg of ixazomib. The median event-free survival (EFS) for the entire study population was 8.4 months; 1-year overall survival was 96%. The EFS was 5.7 months for patients with prior bortezomib exposure and 11.0 months for bortezomib-naïve patients. A grade 3 or 4 adverse event considered at least possibly related to treatment was seen in 11 (32%) patients at 4 mg and in 21 (60%) at 5.5 mg. Dose reductions were more frequent with 5.5 mg dose. Overall, the ixazomib with dexamethasone has good efficacy in relapsed myeloma, is well-tolerated and with higher response rate at 5.5 mg, albeit with more toxicity. This study was registered at www.clinicaltrials.gov as #NCT01415882.

Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study.

PURPOSE: Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. PATIENTS AND METHODS: Eligible patients were adults with newly diagnosed untreated stages II to IV CD20(+) DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. RESULTS: In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). CONCLUSION: R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.

Use of the Functional Assessment of Cancer Therapy--anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia.

BACKGROUND: Anemia is common in myeloproliferative neoplasm (MPN)-associated myelofibrosis. The Functional Assessment of Cancer Therapy (FACT) measurement system is a patient-reported outcomes instrument that documents symptoms of the diverse aspects of cancer treatment. One FACT version, FACT-Anemia (FACT-An), documents symptoms of anemia related to cancer. The FACT-An has been validated in diverse cancer populations, but not in MPN-associated myelofibrosis. OBJECTIVE: Our aim was to evaluate the relationship between anemia response to therapy with pomalidomide with or without corticosteroids and patient-reported outcomes using the FACT-An instrument. METHODS: Data were obtained from a Phase II, randomized, double-blind Bayesian pick-the-winner trial of prednisone and pomalidomide in patients with MPN-associated myelofibrosis and anemia (red blood cell-transfusion dependence). Details of the study, including definitions of anemia, anemia response, red blood cell-transfusion, red blood cell-transfusion dependence, and red blood cell-transfusion independence, are reported. Change in quality of life from randomization to the last cycle of therapy was evaluated using the FACT-An Physical Well Being, Functional Well Being, Trial Outcome Index, and Anemia domains. Clinically important differences were used to determine the smallest difference in scores that patients perceived as beneficial in the FACT-An domains of interest. Patients were classified as meeting clinically important differences for responsiveness if their change score from baseline was >1 SEM, indicating improvement. RESULTS: Eighty-five patients were studied. Thirty-one patients (37%) were classified as anemia responders by prospectively defined criteria. Across all FACT-An domains, anemia responders showed greater improvement in Physical Well Being, Functional Well Being, and Trial Outcome Index scores than did nonresponders. This improvement began at the second 28-day cycle of therapy and was sustained. CONCLUSIONS: We show a correlation between anemia response and improved quality of life measured by the FACT-An instrument in patients with MPN-associated myelofibrosis and anemia.

The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs.

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the U.S. The course of the disease has been shown to be negatively impacted by increased levels of BCL2. Strategies to downregulate BCL2 and shift the balance towards cellular demise are actively being explored. Therefore, we examined whether the investigational agent MLN2238 could inhibit the proteasomal machinery and induce CLL cell death while also downregulating BCL2. MLN2238-induced cell death was studied in peripheral blood mononuclear cells from 28 CLL patients. MLN2238 produced a dose-dependent reduction in BCL2 and CLL cell viability with maximum cell death observed at a 50 nmol/l concentration by 48 h. Annexin-V staining, PARP1 and caspase-3 cleavage along with an increase in mitochondrial membrane permeability were noted after cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. Furthermore, we observed enhanced anti-CLL effects in tumour cells treated with either a combination of MLN2238 and the BH3 mimetic AT-101 or MLN2238 and fludarabine. Together, our data suggest the potential for proteasome inhibitor based therapy in CLL and the rationale design of drug combination strategies based on CLL biology.

AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia.

Multiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL2 and MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Thus, we investigated the anti-tumour effects of a pan-BCL2 inhibitor, AT-101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL2 family members. AT-101 was able to downregulate BCL2 and MCL1 in all plasma cell cancer models and induced apoptotic cell death in a caspase-dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA2, FRZB, FYN, IRF1, PTPN11 genes in LDA-treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.

Hodgkin lymphoma of the maxillary sinus: an unusual occurrence.

The maxillary sinus is a rare anatomic site for Hodgkin lymphoma, as only 1 such case has been previously reported in the literature. Nevertheless, we recommend that lymphoma be considered in the differential diagnosis of a mass that involves the maxillary sinus or any other unusual extranodal site in the head and neck. Lymphoma in a patient who presents with disease in an unusual site and without lymphadenopathy is difficult to diagnose. We report the case of a 60-year-old woman who presented with nasal congestion and obstruction. Examination revealed an abnormal-appearing mucosa involving the maxillary sinus. Subsequent evaluation led to a diagnosis of Hodgkin lymphoma. Because making such a diagnosis is difficult, close attention to radiologic and pathologic findings is important. Our review of the literature revealed that treatment commonly includes chemotherapy and radiotherapy, which yield excellent outcomes. The current standard of care for patients with similar-stage Hodgkin lymphoma at other sites can guide the treatment course for patients with extranodal Hodgkin lymphoma.

Pomalidomide is active in the treatment of anemia associated with myelofibrosis.

PURPOSE: Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. METHODS: In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. RESULTS: Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving > or = 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade > or = 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). CONCLUSION: Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.

The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis.

Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.