7 research outputs found
Mantle Cell Lymphoma in the Thyroid: A Rare Presentation
Background: While 2% of all extranodal Non-Hodgkin Lymphomas present in the thyroid, there exists insufficient data to describe the incidence of mantle cell lymphoma in the thyroid. A case series of 1400 patients revealed that \u3c 1% of thyroid lymphomas may be MCL; hence better understanding of the disease course is essential.
Patient Findings: A 65-year-old female was referred for a multinodular goiter. Multiple fine needle aspirations from the dominant right nodule were consistent with Hashimoto\u27s thyroiditis and flow cytometry was negative. Due to progressing dysphagia, she underwent total thyroidectomy.
Summary: Pathology revealed MCL with mantle zone growth pattern in the right thyroid. Flow cytometry showed monoclonal B cells comprising 9% of total cells. The Ki-67 index was 10%. She was diagnosed as having stage IIE MCL and offered conservative management by medical oncology, given that she had no B symptoms.
Conclusion: Though chemotherapy is the treatment of choice in MCL, a subset of patients with low-grade disease may be observed. As in our patient, mantle zone growth pattern and a Ki-67 index \u3c 10% suggest a favorable prognosis. A diagnosis of primary MCL in the thyroid remains rare and staging modalities as well as treatment options continue to evolve
The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma
Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL cases (8.3% and 7.5%, respectively), but were more widely expressed on TILs in a correlated manner. With median follow-up of 44 months (n = 70, range 5-85), 4-year progression-free survival (PFS) and overall survival (OS) rates were significantly inferior among DLBCL patients with high vs low/negative TIM-3 expression (PFS: 23% [95% CI 7% to 46%] vs 60% [95% CI 43% to 74%], respectively, P = 0.008; OS: 30% [95% CI 10% to 53%] vs 74% [95% CI 58% to 85%], respectively, P = 0.006). Differences in OS remained significant when controlling for International Prognostic Index in Cox regression analyses (HR 3.49 [95% CI 1.40-6.15], P = 0.007). In addition, we observed that co-culture of DLBCL cell lines with primed T cells in the presence of anti-LAG-3 and anti-TIM-3 induced potent dose-dependent increases in in vitro cell death via AcellaTox and IL-2 ELISA assays, suggesting potent anti-tumor activity of these compounds
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Tracheobronchial Tumors: Radiologic-Pathologic Correlation of Tumors and Mimics.
Tracheobronchial masses encompass a broad spectrum of entities, ranging from benign and malignant neoplasms to infectious and inflammatory processes. This article reviews the cross-sectional findings of tracheal tumors and tumor-like entities, correlates imaging findings with histologic pathology, and discusses pearls and pitfalls in accurately diagnosing and classifying tracheal tumors and mimics
Automated red blood cell exchange for acute drug removal in a patient with sirolimus toxicity
Sirolimus is an immunosuppressant used to prevent graft versus host disease in allogeneic hematopoietic stem cell transplant recipients. It has a large volume of distribution (12 +/- 7.5 l/kg) and within the intravascular space approximately 95% of it is bound to red blood cells. Because of potential toxic effects at high trough levels, therapeutic drug monitoring is recommended for sirolimus. We present a case of severe hepatic dysfunction due to Hepatitis B and sirolimus toxicity, in a 51-year-old male stem cell transplant recipient. An automated red cell exchange decreased his blood sirolimus level from 22.6 to 10.3 ng/ml (55% reduction) and improved his liver enzymes. Re-equilibration of sirolimus from other compartments to the blood necessitated a series of four red cell exchanges, after which the sirolimus level was 4.7 ng/ml. Although the patient ultimately succumbed to multiorgan failure, red cell exchange may be considered for acute removal of sirolimus in selected patients
Physiological measurements corroborate symptomatic improvement after therapeutic leukapheresis in a pregnant woman with chronic myelogenous leukemia
Therapeutic leukapheresis can control the white blood cell count (WBC) of pregnant women with chronic myelogenous leukemia (CML) who have hyperleukocytosis without leukostasis. The medical justification for this treatment has not been objectively documented. We report a 27-year-old woman, diagnosed with CML at 10-week gestation, who developed severe dyspnea on exertion. A workup that included chest CT and echocardiography with a bubble study detected no cardiopulmonary pathology to explain her symptoms, and thus she was referred for leukapheresis. Prior to her first leukapheresis, which lowered her WBC from 154 x 103 /muL to 133 x 103 /muL, her oxygen saturation (SpO2 ) on room air decreased from 98 to 93% during 100 feet of slow ambulation and she was dyspneic. Just after the leukapheresis, her dyspnea on exertion was much improved and her SpO2 remained at 98% with repeat ambulation. Spirometry and lung volume studies obtained before and after her first leukapheresis demonstrated 32 and 31% improvements in forced vital capacity and forced expiratory volume in 1 s respectively, a 25% increase in functional residual capacity, and a 142% improvement in expiratory reserve volume. Residual volume decreased by almost 20%. Three times in a week, leukapheresis was continued until her WBC was controlled with interferon alpha-2b approximately 4 weeks later. Her dyspnea had completely resolved. She gave birth by elective caesarean section to a healthy boy at 32 weeks. Corroboration of symptom relief by leukapheresis with physiological data may justify such treatment in pregnant patients with CML
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A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up
Abstract
Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile.
Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually.
Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity.
Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting.
Disclosures
Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding
Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.
Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification