Prognostic value of visual IMPeTUs criteria and metabolic tumor burden at baseline [18F]FDG PET/CT in patients with newly diagnosed multiple myeloma.

BACKGROUND: 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography combined with low-dose computed tomography (PET/CT) can be used at diagnosis to identify myeloma-defining events and also provides prognostic factors. The aim of this study was to assess the prognostic significance of baseline [18F]FDG PET/CT visual IMPeTUs (Italian myeloma criteria for PET Use)-based parameters and/or total metabolic tumor volume (TMTV) in a single-center population of patients with newly diagnosed multiple myeloma (NDMM) eligible for transplantation. METHODS: Patients with MM who underwent a baseline [18F]FDG PET/CT were retrospectively selected from a large internal database of the University Hospital of Liege (Liege, Belgium). Initially, all PET/CT images were visually analyzed using IMPeTUs criteria, followed by delineation of TMTV using a semi-automatic lesion delineation workflow, including [18F]FDG-positive MM focal lesions (FL) with an absolute SUV threshold set at 4.0. In a first step, to ensure PET/CT scans accurate reporting, the agreement between two nuclear medicine physicians with distinct experience was assessed. In the second step, univariable and multivariable analyses were conducted to determine the prognostic significance of [18F]FDG PET/CT parameters on progression free survival (PFS) and overall survival (OS), respectively. RESULTS: A total of 40 patients with NDMM were included in the study. The observers agreement in the analysis [18F]FDG PET/CT images was substantial for the presence of spine FL, extra spine FL, at least one fracture and paramedullary disease (Cohen's kappa 0.79, 0.87, 0.75 and 0.64, respectively). For the presence of skull FL and extramedullary disease the agreement was moderate (Cohen's kappa 0.56 and 0.53, respectively). Among [18F]FDG PET/CT parameters, a high number of delineated volumes of interest (VOI) using the SUV4.0 threshold was the only independent prognostic factor associated with PFS [HR (95% CI): 1.03 (1.004-1.05), P = 0.019] while a high number of FL (n > 10; F group 4) was the only independent prognostic factor associated with OS [HR (95% CI): 19.10 (1.90-191.95), P = 0.01]. CONCLUSION: Our work confirms the reproducibility IMPeTUs criteria. Furthermore, it demonstrates that a high number of FL (n > 10; IMPeTUs F group 4), reflecting a high [18F]FDG-avid tumor burden, is an independent prognostic factor for OS. The prognostic value of the TMTV delineated using a SUV4.0 threshold was not significant. Nevertheless, the count of delineated [18F]FDG-avid lesions VOI using a SUV4.0 threshold was an independent prognostic factor for PFS.

Hereditary leiomyomatosis and acute lymphoblastic leukemia: A link through fumarate dyshydratase mutation?

BACKGROUND: : Hereditary leiomyomatosis (HL) is an autosomal dominant condition due to a variety of fumarate hydratase (FH) mutations in which individuals tend to develop cutaneous leiomyomas, multiple uterine leiomyomas and are at risk for developing aggressive papillary renal cell carcinoma. CASE PRESENTATION: : A 26-year-old man with a past history of acute lymphoblastic leukemia (T-ALL) presented with numerous painful light brown papules and nodules spread all over his body except for the head, appearing since infancy. Similar lesions were present in his mother's family. A cutaneous biopsy revealed a cutaneous leiomyoma. His mother died from metastatic uterine neoplasia and his sister suffered from leiomyoma of the uterus. No renal cancer was reported in his family. A heterozygous pathogenic variant was detected in the FH gene. CONCLUSION: : To our knowledge, this is the first case possibly linking HL and T-ALL through FH deficiency.

Angioimmunoblastic T-Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Novel Form of Composite Lymphoma Potentially Mimicking Richter Syndrome.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent small B-cell neoplasm that may transform into a clinically aggressive disease, namely Richter syndrome, usually as diffuse large B-cell lymphoma. Besides, CLL/SLL encompasses an increased risk of developing other secondary cancers, including a variety of T-cell lymphomas, often of the anaplastic large-cell type or with a cytotoxic phenotype. Here, we report a small series of patients with composite lymphomas consisting of CLL/SLL and angioimmunoblastic T-cell lymphoma (AITL), a hitherto unrecognized association. The 3 patients (1 male/2 females, 68 to 83 y) presented with high-grade-type symptoms. One patient was clinically suspicious for Richter syndrome, in the others CLL/SLL and AITL were concomitant de novo diagnoses. CLL/SLL and AITL were admixed in the same lymph nodes (3/3 cases) and in the bone marrow (1/2 cases). In all cases, the AITL comprised prominent clear cells with a strong T follicular helper immunophenotype and similar mutations consisting of TET2 or DNMT3A alterations, IDH2 R172K/M, and RHOA G17V. The 3 patients received chemotherapy. One died of early AITL relapse. The other 2 remained in complete remission of AITL, 1 died with recurrent CLL, and 1 of acute myeloid leukemia. These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation.

Dual-tracer PET/CT scan after injection of combined [18 F]NaF and [18 F]FDG outperforms MRI in the detection of myeloma lesions.

The detection rates of whole-body combined [18 F]NaF/[18 F]FDG positron emission tomography combined with computed tomography (PET/CT), CT alone, whole-body magnetic resonance imaging (WB-MRI), and X-ray were prospectively studied in patients with treatment-requiring plasma cell disorders The detection rates of imaging techniques were compared, and focal lesions were classified according to their anatomic location. Twenty-six out of 30 initially included patients were assessable. The number of focal lesions detected in newly diagnosed patients (n = 13) and in relapsed patients (n = 13) were 296 and 234, respectively. The detection rate of PET/CT was significantly higher than those of WB-MRI (P < 0.05) and CT (P < 0.0001) both in patients with newly diagnosed and in those with relapsed multiple myeloma (MM). The X-ray detection rate was significantly lower than those of all other techniques, while CT detected more lesions compared with WB-MRI at diagnosis (P = 0.025). With regard to the infiltration patters, relapsed patients presented more diffuse patterns, and more focal lesions located in the limbs compared with newly diagnosed patients. In conclusion, the detection rate of [18 F]NaF/[18 F]FDG PET/CT was significantly higher than those of CT, MRI, and X-ray, while the detection rate of X-rays was significantly lower than those of all other imaging techniques except for focal lesions located in the skull.

[What is new in the management of multiple myeloma]. / Nouveautés dans la prise en charge du myélome.

Multiple myeloma is the second most frequent hematological malignancy. Unfortunately, it is still incurable. A better understanding of the myeloma pathophysiology favored the development of new therapeutic molecules that improved both survival and quality of life of patients. Diagnostic and prognostic criteria for myeloma have been reviewed and help to detect multiple myeloma more early and further help to define the best therapeutic strategy. These new regimens are associated with side effects that differ from those of classic molecules and that we have to be able to recognize and to treat appropriately.

Le myélome multiple est le second cancer hématologique le plus fréquent. Il reste malheureusement incurable à l'heure actuelle. Pourtant, ces deux dernières décennies ont été marquées par des progrès dans la compréhension de la physiopathologie du myélome, ce qui a permis le développement de nouvelles molécules thérapeutiques, améliorant la survie et la qualité de vie des patients. Les critères diagnostiques et pronostiques du myélome ont été revus et sont maintenant plus performants pour détecter des stades précoces et déterminer ainsi la stratégie thérapeutique à entreprendre. Les nouveaux régimes de traitement sont grevés d'un profil d'effets secondaires différent qu'il faut pouvoir reconnaître et traiter.

A First Report on [18F]FPRGD2 PET/CT Imaging in Multiple Myeloma.

An observational study was set up to assess the feasibility of [18F]FPRGD2 PET/CT for imaging patients with multiple myeloma (MM) and to compare its detection rate with low dose CT alone and combined [18F]NaF/[18F]FDG PET/CT images. Four patients (2 newly diagnosed patients and 2 with relapsed MM) were included and underwent whole-body PET/CT after injection of [18F]FPRGD2. The obtained images were compared with results of low dose CT and already available results of a combined [18F]NaF/[18F]FDG PET/CT. In total, 81 focal lesions (FLs) were detected with PET/CT and an underlying bone destruction or fracture was seen in 72 (89%) or 8 (10%) FLs, respectively. Fewer FLs (54%) were detected by [18F]FPRGD2 PET/CT compared to low dose CT (98%) or [18F]NaF/[18F]FDG PET/CT (70%) and all FLs detected with [18F]FPRGD2 PET were associated with an underlying bone lesion. In one newly diagnosed patient, more [18F]FPRGD2 positive lesions were seen than [18F]NaF/[18F]FDG positive lesions. This study suggests that [18F]FPRGD2 PET/CT might be less useful for the detection of myeloma lesions in patients with advanced disease as all FLs with [18F]FPRGD2 uptake were already detected with CT alone.

Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation: a prospective multicenter randomized trial.

We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 µg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery.

Diagnosis and follow-up of monoclonal gammopathies of undetermined significance; information for referring physicians.

The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.

Clinical characteristics and outcome of isolated extracerebral relapses of primary central nervous system lymphoma: a case series.

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort.

[Clinical indications of radioimmunotherapy in lymphoma]. / Indications cliniques de la radiothérapie métabolique dans les tymphomes.

In their later stages low grade lymphoma are incurable. These lymphomas being radio-sensitive, a treatment of metabolic radioimmunotherapy, using monoclonal antibodies (anti-CD20) as the carrier has been developed. The aim of this treatment is to use these antibodies to target radiation to tumor tissues while limiting toxicity to normal cells. Ibritumomab tiuxetan (Zevalin) is currently prescribed for patients with relapsed or refractory low-grade follicular lymphoma after rituximab treatment. This outpatient treatment has a high level of overall response rate including complete response and that for a long period. The side effects are essentially hematological and reversible. In the near future many more indications should become apparent and Zevalin should become an important tool in the B-cell lymphoma (low and high grade).

Distinct clonal origin in two cases of Hodgkin's lymphoma variant of Richter's syndrome associated With EBV infection.

Occurrence of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL), clinically referred to as Richter's syndrome, occasionally manifests as a lymphoproliferation resembling Hodgkin's lymphoma (HL) and often containing the Epstein-Barr virus (EBV). Only a limited number of HL variants have been subject to informative analysis regarding their clonal relationship to the CLL, with evidence of a same clonal origin in some cases and of clonally unrelated neoplasms in other cases. In this paper, we performed a detailed pathologic, virologic, and molecular analysis of two cases of Richter's syndrome with HL features. The first case occurred in a 65-year-old man with a 5-year history of CLL as a mediastinal and supraclavicular mass histologically diagnosed as lymphocyte depleted HL with no background CLL. The second case occurred in a 78-year-old woman with a 4-year history of CLL as an inguinal mass with a composite histologic appearance comprising areas of CLL, areas of CLL with Hodgkin Reed-Sternberg cells, and areas of HL. Both patients had received fludarabine therapy. The HRS cells were CD20-/CD30+/CD15-/J-chain- in case no. 1 and CD20+/-/CD30+/CD15-/J-chain- in case no. 2. In both cases, the Hodgkin's Reed-Sternberg cells (HRS) were positive for type A EBV, and a 30-bp deletion of the LMP-1 gene was detected in case no. 2. Using microdissection and polymerase chain reaction amplification of the immunoglobulin heavy chain gene (IgH) complementarity determining region III of each cell type, we demonstrated a distinct clonal origin for the CLL cells and the HRS in both cases. These cases bring support to the hypothesis that EBV+ HL in CLL patients occurs as unrelated secondary neoplasms most likely as the result of the immune depression associated with CLL and also raise the question of a possible causal role of fludarabine.