Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043 patient/years analysis.

Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anti-complement treatment has revolutionized the natural history of PNH with control of the hemolytic process and abolition of thrombotic events (TE). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anti-coagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anti-coagulants (DOACs). Herein, we accrued a large real-world cohort of PNH patients from four US centers to explore features, predictors of TE and anti-coagulation strategies. Among 267 patients followed-up for a total of 2043 patient/years, 56 (21%) developed TE. This occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TE was halved in patients receiving complement inhibitors (21 vs 40 TE per 1000 patient/years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3% respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (>2 mutations or less) and variant allelic frequency of PIGA mutations. Anti-coagulation with warfarin (39%), DOACs (37%), and low-molecular-weight heparin (16%) was administered for a median of 29 months (9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (8.9-45) while 14 cases discontinued anti-coagulation without TE recurrence at a median time of 51.4 months (29.9-86.8).

Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk.

Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92-88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06-55.35, P < 0.001). Currently, the 'zygosity' of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include 'zygosity' status of CHIP mutations and that future prognostication systems should take mutation 'zygosity' into account.

Primary Malignant Melanoma of the Esophagus in a 76-Year-Old Female.

Mucosal melanomas represent about 1% of all melanoma cases. Primary malignant melanoma of the esophagus (PMME) is a rare and deadly condition, with only about 339 cases reported in the literature. Esophageal melanoma usually presents with progressively worsening dysphagia, and patients often present late in the disease course. Esophageal melanoma can be treated with surgical resection, chemotherapy, targeted therapy, or immunotherapy depending on the stage and tumor mutations. However, due to the rarity of the disease, no trials have been performed to deliver a gold standard of treatment. We present the case of a 76-year-old female who was diagnosed with metastatic primary malignant melanoma of the esophagus and underwent treatment with nivolumab, a PD-1 receptor antagonist.

Current Approach to Managing Patients with Newly Diagnosed High-Risk Multiple Myeloma.

PURPOSE OF REVIEW: With rapid advances in the therapeutic landscape and biological insights in multiple myeloma, it is critical to identify and strategically manage high-risk patients to achieve best outcomes with currently available drugs. The purpose of this review is to summarize the management of high-risk myeloma with a focus on recent advances in the field. RECENT FINDINGS: The most widely accepted definition of "high-risk" is the Revised International Staging System (R-ISS) stage 3 disease, which includes high tumor burden (ISS stage 3) and high-risk FISH cytogenetics or an elevated lactate dehydrogenase level. A major advance in the management of high-risk patients is insight into the importance of achieving and sustaining minimal residual disease (MRD) negativity, which is an influential equalizer for long-term outcomes. Quadruplet pre-transplant induction regimens incorporating an anti-CD38 monoclonal antibody (mAb), proteasome inhibitor (PI: bortezomib or carfilzomib), lenalidomide, and dexamethasone should be strongly considered in high-risk patients given higher odds of getting to MRD negativity with these regimens compared to triplets. In transplant-eligible patients, upfront transplant does lead to a higher rate of sustained MRD negativity and superior PFS compared to delayed transplant. The role of tandem transplant in the context of bortezomib-lenalidomide-dexamethasone (VRD) induction therapy is unclear. Post-transplant maintenance therapy should include lenalidomide in combination with either bortezomib or carfilzomib until progression. For transplant-ineligible patients, VRD or daratumumab-lenalidomide-dexamethasone (DRD) until progressions are both reasonable and choice should be individualized based on patient-related factors. Outcomes of high-risk myeloma patients have improved in the last decade with the use of modern 3-drug induction regimens incorporating a PI and an immunomodulatory drug, with potential for further improvement as we bring anti-CD38 mAb upfront. MRD assessment will play a major role in treatment modification at several key time-points in the future such as pre-transplant, pre-maintenance, and yearly on maintenance therapy.

Venous thromboembolism risk with contemporary lenalidomide-based regimens despite thromboprophylaxis in multiple myeloma: A systematic review and meta-analysis.

BACKGROUND: Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma. METHODS: The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model. RESULTS: The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles). CONCLUSIONS: Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

Primary Care Physician Perspectives on Caring for Adult Survivors of Hematologic Malignancies and Hematopoietic Cell Transplantation.

BACKGROUND: Primary care physicians (PCPs) may face barriers to caring for hematologic malignancy and hematopoietic cell transplantation (HCT) survivors. METHODS: A Web-based survey consisting of 40 questions and 2 case scenarios was administered to 302 PCPs at 2 large integrated health care systems. The questionnaire assessed perceived barriers to delivery of care to hematologic malignancy/HCT survivors, resources available to care for cancer survivors, practices for care coordination with hematologist-oncologists, and preferred models of care delivery. RESULTS: Overall response rate was 30% (n = 86). PCPs reported several barriers such as lack of resources to facilitate care (69%), lack of awareness of screening/prevention guidelines (55%) and psychosocial needs of survivors (65%), inadequate time (65%), and patient preference to follow up with their oncologists (66%). They expressed confidence in caring for general medical issues (84%) and general cancer screening (73%), but they preferred that oncologists manage cancer-related medical issues (42%) as well as screen for cancer recurrence (52%) and secondary cancers (55%). In multivariable analysis, PCPs who had previously cared for a large number of hematologic malignancy/HCT survivors and those with a longer time since graduation from medical school had greater confidence in managing cancer-related medical issues. CONCLUSION: PCPs report several barriers in providing care to hematologic malignancy/HCT survivors. Clinical experience with this patient population is associated with greater confidence in providing survivorship care. Several barriers identified by PCPs in providing survivorship care to hematologic malignancy/HCT survivors are potentially addressable by education and clinical decision support tools and guidelines, thereby enhancing the patients' clinical experience and care coordination with hematologist-oncologists.