Extramedullary Organ Involvement Research Articles

BPDCN: state of the art.

The emergence of blastic plasmacytoid dendritic cell neoplasm (BPDCN) as its own distinct entity within the pantheon of hematologic malignancies is due to the growing understanding of its unique multiorgan clinical presentation and characteristic skin lesions. The occurrence of BPDCN is generally heralded by a multicompartmental presentation of violaceous cutaneous lesions, involvement by bone marrow and/or blood, lymph node invasion, and an inclination toward extramedullary organ involvement, including, most remarkably, central nervous system (CNS)/cerebrospinal fluid positivity. With a median age historically of ≥ 70 years and up to 5:1 male predominance in most of the field's earlier studies, the most notable development in the modern era is the recognition of emerging important groups with BPDCN, such as female, pediatric, and adolescent/young adult patients; CNS + BPDCN patients; and an increasing number of cases being diagnosed worldwide. These trends are in line with the increased educational and research efforts, greater international collaboration, and markedly improved diagnostic tools and clinical approaches among hematology/oncology, hematopathology, dermatology, and dermatopathology teams around the world. Now, with over 5 years since the first commercially approved targeted agent specifically dedicated for BPDCN, the CD123-targeted agent tagraxofusp, improvements have been demonstrated particularly in the frontline setting for patients with BPDCN. The field is abundant with hope, as it has experienced advancements including greater molecular characterization, expanded identification of potential targets for therapy beyond CD123, advent of combination therapies, improving parameters for stem cell transplantation, and novel clinical trials specifically available for patients with BPDCN.

Role of 2-(fluorine-18) Fluoro-2-deoxy-D-glucose Positron Emission Tomography/Computed Tomography in Initial Staging and Bone Marrow Involvement Prediction in Patients with Newly Diagnosed Lymphoma in Correlation with Bone Marrow Study.

Lymphoma is a common malignant proliferative disease in which bone marrow infiltration will upstage the disease and thus affect prognosis of the disease. As of now bone marrow biopsy is considered as a reference standard to find out bone marrow involvement in lymphoma. Performing an invasive and painful intervention in all newly diagnosed lymphoma patients is controversial. PET-CT is a non-invasive technique that gives functional information about the cells using the glucose metabolism. It can detect early bone marrow and extra medullary organ involvement which can lead to restaging of the disease. These advantages make PET-CT a valuable adjunct in diagnosis of lymphoma. Our study aims to evaluate the usefulness of 18 F-FDG PET-CT, a non-invasive, semi quantitative whole body imaging technique for detection of early bone marrow and extra medullary organ involvement in lymphoma patients which in turn can obviate the need for bone marrow study (BMS). The primary objective of study is to categorise FDG uptake in bone marrow as diffuse /unifocal /multifocal / no uptake and to correlate pattern of FDG uptake to bone marrow study. Our study also assesses the role of FDG PET/CT in staging of lymphoma. Thirty patients with newly diagnosed lymphoma in the age group 18 to 75 years of both sexes within 3 months of diagnosis and who have not been started on any treatment was included in the study. Marrow uptake on FDG PET/CT has been categorized as diffuse, unifocal, multifocal and no uptake. Agreement between bone marrow study and FDG PET/CT has been assessed by reliability analysis using Cohen's kappa. Sensitivity, specificity, PPV, NPV of PET/CT in detecting marrow involvement have been calculated. The sensitivity, specificity, PPV, NPV and accuracy of 18 F-FDG PET-CT in detecting marrow involvement of lymphoma cases are 86.6%, 77.7%, 68.4%, 91.3% and 80.9% respectively. 18 F-FDG PET-CT detected bone marrow involvement in 86.6% (13 out of 15 total positive cases) cases of lymphoma which included both HL and NHL. Reliability analysis using Cohen's kappa is used to test the agreement between bone marrow study and 18F-FDG PET/CT. k value of 0.6 was obtained which showed a moderate agreement between bone marrow study and 18F-FDG PET/CT in marrow assessment. 18F-FDG PET/CT is a highly sensitive imaging modality which can pick up extra-nodal organ and BMI in patients with lymphoma and can upstage the disease and alter treatment strategies. PET-CT cannot completely replace the bone marrow study. However, being an invasive painful procedure, BMB can be avoided in cases with unifocal or multifocal marrow involvement on PET-CT.

Unicentric Retrospective Analysis of 130 Patients with Extramedullary Multiple Myeloma (EMM)

CONCLUSION Despite the development of new agents and the widespread use of hematopoietic cell transplantation (HCT), the prognosis of patients (pts) with multiple myeloma and extramedullary involvement (EMM) is rather unfavorable. Until now, there are no generally accepted standards for diagnosis and treatment of EMM. We performed a retrospective analysis of 130 pts with EMM treated at Klinikum Chemnitz between 2007 and 2022. Various demographic and clinical factors were recorded in a database and evaluated for their impact on response and survival. The data cut point was July 2022, and for follow-up a minimum of 3 months was required. One hundred and thirty pts (89 men, 41 women) with EMM at a median age of 68 years (range, 37-87 years) were included. In 78 pts extramedullary involvement was detected at the time of initial diagnosis (primary EMM), and in the remaining 52 pts a secondary EMM was diagnosed at the time of relapse (n=38) or refractory disease (n=14). In approximately two-thirds of pts EMM manifested exclusively in the paraskeleton (n=84), while roughly one-third of pts showed an extramedullary organ involvement (n=25), or both (n=21). Cytogenetic data were available in 125 pts, with 39 pts classified as high-risk EMM (including del17p in 11 pts). ISS could be evaluated in only 56 pts, of whom 22 pts had ISS III. Elevated serum LDH levels were observed in almost half of the pts (n=63) at the time of EMM diagnosis. Treatment regimens included mainly proteasome inhibitors (n=106), immunomodulatory drugs (n=74) and CD38 antibodies (n=42). Fifty-five pts (42.3%) received autologous (n=44), allogeneic (n=8) or autologous-allogeneic HCT (n=3). Serologic response to treatment (at least PR) according to IMWG criteria was 63.8% (83/130) and imaging response was 56.9% (74/130). With a median follow-up of 84.2 months, median progression-free survival was 10.3 months and median overall survival was 23.8 months. In univariate analysis for PFS and OS, we found significantly worse outcomes in patients with secondary EMM (vs. primary EMM), EMM with organ manifestation (vs. paraskeletal EMM only), ISS III (vs. ISS I +II), and elevated serum LDH (vs. not elevated). Furthermore, pts with del17p had significantly shorter PFS, while detection of ampl1q32 (n=14) was associated with significantly worse OS. For other tested factors [lambda light chain involvement, t(14;16), dupl1q21 or tripl1q21, EMM diagnosis 2007-2013 vs. 2014-2022] we found no negative effects on PFS or OS. Multivariate Cox regression analysis confirmed secondary EMM as an independent negative factor for PFS (HR 3.62, p<0.0001) and OS (HR 2.95, p<0.0001), whereas detection of del17p was only associated with unfavorable PFS (HR 2.02, p=0.03). Our data show that the prognosis of pts with EMM remains poor. Despite the introduction of many innovative agents, outcomes have not improved significantly since 2013. There is an urgent need for diagnostic/therapeutic guidelines of EMM as well as risk-adapted therapeutic strategies (using modern immunotherapies and cell therapies).

Impact of newly diagnosed extramedullary myeloma on outcome after first autograft followed by maintenance: A CMWP-EBMT study.

No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy. We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p = .69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib. The median follow-up from maintenance start was 44 months. Three-year progression-free survival (PFS) was 52% (48%-57%) for no EMD, 56% (44%-69%) for paraskeletal involvement, and 45% (22%-68%) for organ involvement (p = .146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three-year overall survival (OS) was 81% (77%-84%), 88% (80%-96%), and 68% (47%-89%; p = .064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD. Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start.

Clinical Features and Outcomes of Light-Chain Dominant Multiple Myeloma: A Population-Based Study

Background: There is a certain subgroup of multiple myeloma(MM) patients shows serum and urine monoclonal protein level that is negative or below thresholds considered to be measurable (Oligosecretory and non-secretory MM). In this subgroup the serum free-light-chain (FLC) assay can be used to monitor treatment response if the patient shows abnormal FLC ratio and more than 100 mg/L of involved FLC level. Yet studies about treatment outcome and clinical features in this particular patient group are still lacking. We aimed to conduct a population based study about light-chain dominant MM (LcDMM) in Korea.Methods: We performed a single-center retrospective study based on the MM patients referred to the Hematology Unit of Seoul National University Hospital from 2005 to 2015. LcDMM was defined as oligosecretory or non-secretory MM with more than 1,000 mg/dL of involved light chain. We analyzed for demographic and clinical characteristics as well as overall survival (OS) and progression free survival(PFS). Also we wanted to see whether there was a difference between characteristics of kappa and lambda LcDMM.Results: A total of 157 LcDMM cases were identified including 37 (23.5%) patients with non-secretory MM. Comparing with previously published general MM population data. LcDMM patients were younger (Median age at diagnosis = 60 years, with 66.2% of diagnosed patients being <60 years) and showed higher proportion of female (Male 51.6%). The International Staging System (ISS) distribution in stage I, II, and III was 40.4%, 19.9% and 39.7%. Among patients with available cytogenetic data, half of the patients had normal karyotype (49.0%) and the prevalence of several cytogenetic abnormalities with poor prognosis including t(4;14), del(17/17p) and t(14;16) was 1.9%, 7.0%, and 1.3% respectively.More than half of the patients were lambda-FLC involved MM (54.8%). Half of the lambda. LcDMM was ISS stage II at diagnosis (46.2%), and in contrast, half of the kappa LcDMM was Stage I (48.5%). The incidence of extramedullary organ involvement was not significantly different between kappa and lambda LcDMM. The median overall survival (OS) from diagnosis of whole LcDMM patients was 59.4 months and of each (ISS) stage was 62 months, 57 months, and 44 months in Stage I, II and III. The median OS of kappa and lambda LcDMM was 69.2 months (95% confidence interval (CI) = 38.6 to 99.7) and 40.3 months (95% CI = 16.4 to 64.1), but there was no statistically significant difference (Plogrank = 0.317)Previous exposure to thalidomide, lenalidomide, and bortezomib was 56.7% (n=89), 21.7% (n=34), and 72.3% (n=112), respectively, and 43.9% (n=69) of patients underwent hematopoietic stem cell transplantation (HSCT). Median PFS of kappa and lambda LcDMM after thalidomide treatment was 11.8 months vs 5.5 months. After lenalidomide treatment, median PFS was not reached yet. In bortezomib, lambda LcDMM showed higher median PFS than kappa LcDMM (9.0 vs 30.0). But, again, there was no statistically significant difference (Plogrank =0.214, 0.506, 0.786)Conclusion : Patients with LcDMM shows several clinical characteristics that clearly is distinguished from secretory MM. In general, the type of light chain is known to have no effect on the prognosis of MM. Yet there was a certain tendency of worse prognosis to lambda FLC involved patients in this study, and bortezomib might be considered for better response in this population. There is a limitation in statistical power of this study due to small population. But this is the largest population based study of all previously published single-center oligosecretory or non-secretory MM study and is also the first study on Asian population. DisclosuresNo relevant conflicts of interest to declare.

Mastocytosis.

The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists. The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN). Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases. In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.

Abstract 1417: Development of a miRNA-based prediction tool to discriminate cutaneous blastic plasmacytoid dendritic cell neoplasm from cutaneous myeloid sarcoma

Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myeloid sarcoma (MS) are two extremely rare and aggressive hematological diseases. Both malignancies most commonly arise with skin lesions with or without extramedullary organ involvement before leukemic dissemination. Given its rarity and less known biology, in some cases with defective/ambiguous phenotype distinguish between these two entities may be challenging for pathologists and clinicians.1 Can the machine learning predictive model help to solve this diagnostic question? Here we performed the first study of microRNA (miRNA) profiling of BPDCN and MS in order to 1) Discover new molecular features selectively driving BPDCN respect to MS 2) Develop a machine learning based-prediction tool useful for discriminating BPDCN and MS. Methods We performed miRNA profiling (NanoString Technologies) of cutaneous biopsies of 16 BPDCN and 23 MS cases. Using Supervised Analysis, we identified 49 miRNAs differentially expressed that were randomly validated by qRT-PCR and next interrogated by functional enrichment analysis. Finally, a machine learning algorithm based on Linear Discriminant Analysis2 was applied to identify candidate miRNAs able to discriminate BPDCN from MS cases. Results In line with the overlapping clinical features of BPDCN and MS, the molecular profiling of these two diseases was proved to be extremely similar. Unsupervised Analysis well demonstrated that the miRNA profiles of the two malignancies are closely related and indeed, BPDCN and MS cases cluster together. When a Supervised Analysis was applied, we identified a set of 49 miRNAs differentially expressed in BPDCN respect to MS, 25 down- and 24 up-regulated. Of relevance, down-regulated miRNAs were predicted to be markedly involved in the apoptosis regulation of BPDCN. Machine learning predictive model identified a set of 12 miRNAs (5 up and 7 down) able to discriminate cutaneous BPDCN from MS. Conclusion This is the first miRNA profiling study in BPDCN and MS that showed how strongly these two diseases overlap at molecular level. Despite their similarity, BPDCN cases displayed a set of miRNAs significantly down-regulated when compared to MS, with possible dysregulation of cell death pathway. Of practical interest, we designed a machine learning predictive model based on the expression of 12 miRNAs, which alone may be applied to distinguish between the two hematological diseases. This tool, if validated in a larger set of cases, may help to differentiate BPDCN and MS in cases with defective/ambiguous phenotype.

A study on clinical, immunophenotypic pattern in pediatric acute leukemias in a teaching hospital

Background: Acute leukemia contributes to nearly one third of the pediatric malignancies. For effective management of a curable malignancy, the epidemiology of childhood leukemias and audit of previously treated patients would be required. The objective was to study the clinical and immunophenotypic pattern of acute leukemia in children &lt;12 years of age admitted in a tertiary centre. Methods: Prospective study done on 31 children, diagnosed as leukemia and treated over a period of 3 years in GRH, Madurai. Detailed history analysis, clinical examination, lab investigations including flowcytometry were done.Results: ALL was the most common acute leukemia in children (90.3%). 85.7% were identified as B-cell and 14.3% as T-cell. Of the B-ALL, 87.5% was pre-B, 8.3% pro-B and 4.2% mature B ALL. Myeloid antigen co-expression was seen in 35.7%. Fever was the most common symptom (87%) and hepatosplenomegaly was the most common sign (&gt;90%). Poor outcome was noted in 42.3%. T-cell appeared to have worse prognosis than B-cell but did not retain independent prognostic significance in univariate analysis.Conclusions: B-ALL was more common than T-ALL. Extra medullary organ involvement indicates increased tumor burden and poor outcome. None of the clinical or laboratory parameters appeared to predict poor outcomes in our study and this may be due to small sample size. This study provides an insight into the data regarding the epidemiology, clinicopathologic feature and outcome of acute leukemia in a center with low resource settings.

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT

We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both).

Multiple Myeloma Presenting as Acute GI Bleed and Adynamic Colon

Introduction: Multiple myeloma (MM) is a monoclonal plasma cell neoplasm of the bone marrow that produces specific immunoglobulin (Ig). Extramedullary organ involvement is very rare; characterized by infiltrative disease inform of amyloidosis or plasmacytoma. Gastrointestinal amyloidosis (GIA) results from either mucosal or neuromuscular infiltration. Systemic amyloid deposition are mostly AL or AA amyloid caused by a plasma cell dyscrasia or recurring inflammation, respectively. Herein, we present a case of patient who initially presented with GI bleed constipation due to GIA - AL. Case: 64 y/o female with a history of atrial fibrillation, h/o bleeding gastric ulcer on pantoprazole presented to ED for elective ablation. Her physical exam and VS were within normal limits. Hospital course was complicated by melena. Patient had an upper and lower endoscopy which found an ulcerated antral mass with heaped up edges (Forest Class III) and external hemorrhoids, respectively. Biopsy of the antral mass did not identify malignancy. After failure to resolve on empiric PPI therapy, the repeat biopsy was stained for amyloid. (image 1). Bone marrow biopsy revealed, multiple myeloma with Immunofixation significant for IgG kappa monoclonal protein. Patient was started on chemotherapy. Patient was readmitted after two months with nausea, vomiting, and obstipation after failing outpatient regimen of poly-ethylene glycol (PEG)and fleet enemas for 5 days. Physical exam was significant for distended abdomen with hypoactive bowel sounds. CT scan abdomen and pelvis revealed fecal material throughout colon with a possible transition point at sigmoid colon. Patient improved after manual disimpaction. Colonoscopy did not find any evidence of colonic obstruction, but patchy ulcerated mucosa was biopsied. The biopsies revealed presence of thickened muscularis mucosa due to amyloid deposition (Image 2). Patient was discharged home on linaclotide and daily PEG with relief. Discussion: This case highlights an atypical presentation of multiple myeloma in form of amyloidosis, gastric hemorrhage with progressive colonic atony despite initiation of chemotherapy. Symptomatic GIA can present as bleeding, malabsorption, or protein-losing enteropathy; however gastrointestinal dysmotility is a very uncommon presentation. The presence of GIA should prompt a search for possible etiologies such as MM. Staining for amyloid should be considered in a patient with unresolved GI inflammation.Figure: Gastric antrum(endoscopy with Histology).Figure: Descending colon(Colonoscopy and histology).

Treatment of blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4+CD56+CD123+lineage-MPO-, although many patients will present with variable expression of CD4, CD56, or alternate plasmacytoid markers, which compounds the difficulty in differentiating BPDCN from other myeloid or lymphoid malignancies. Chromosomal aberrations are frequent, and the mutational landscape of BPDCN is being rapidly characterized although no obvious molecular target for chemoimmunotherapy has been identified. Chemotherapy regimens developed for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome have all been used to treat BPDCN. Relapse is frequent, and overall survival is quite poor. Allogeneic transplantation offers a chance at prolonged remission and possible cure for those who are eligible; unfortunately, relapse remains high ranging from 30% to 40%. Novel therapies such as SL-401, a diphtheria toxin conjugated to interleukin-3 (IL-3) is commonly overexpressed in BPDCN and other aggressive myeloid malignancies and has shown considerable promise in ongoing clinical trials. Future work with SL-401 will define its place in treating relapsed or refractory disease as well as its role as a first-line therapy or bridge to transplantation.

Detection of Translocation t(7;12)(q36;p13) in Infants with Acute Myeloid Leukemia By Novel 3-Color Fluorescent in Situ Hybridization Approach

Background. Translocation t(7;12)(q36;p13) leading to MNX1 (HLXB9)-ETV6 fusion gene formation is recurrent chromosomal rearrangement, predominantly found in children under 24 months of age with acute myeloid leukemia (AML) and associated with dismal outcome. In the majority of cases t(7;12) is cryptic and can be detected by fluorescent in situ hybridization (FISH) only.Purpose. To evaluate the incidence of t(7;12)(q36;p13) and initial clinical parametres and treatment outcome of infant with AML carrying t(7;12) using novel 3-color FISH approach.Methods. 81 infants with de novo AML who was diagnosed between June 1999 and December 2014 were included in the current study. Median age in the observed group of patients was 6.9 months (range 0.3-11.7). Bone marrow morphology was done in all cases flow cytometry in 67 cases. FAB variant was available in 72 patients. Chromosomal banding analysis (CBA) were performed in all cases, while RT-PCR for the most common fusion gene transcripts (MLL rearrangements, RUNX1-RUNX1T1, PML-RARa, CBFB-MYH11, BCR-ABL1) were done in 52 cases, FISH for MLL rearrangements in 49 cases. All MLL-negative cases were screened for t(7;12) by novel 3-color FISH approach consisted of a break-apart probe composed of an orange labeled probe centromeric to the ETV6 gene in 12p13, a green labeled probe telomeric to ETV6 together witha probe combination made of two loci flanking the HLXB9 gene, both labeled in blue. All probes were applied simultaneously and constituted the 3-color probe set used as a novel approach in this study. All probes was synthesized on our demand by MetaSystems (Germany) and applied partly retrospectively, partly -from March 2012 - prospectively to available patients material. Written informed consent was obtained at all cases.Results. Among 81 included patients there were 80 cases of AML and 1 case of Biphenotypic acute leukaemia (BAL). Various 11q23/MLL rearrangements were revealed in 45 cases (55.6%); inv16 in 3 cases (3.7%), including 1 case of simultaneous detection of inv16 and t(7;12); t(1;22)(p13;q13) was found 5 cases (6.2%); complex karyotype in 5 cases (6.2%); t(7;12)(q36;p13) in 6 cases (7.4%); other cytogenetic aberrations and normal karyotype in 9 cases (11.1%) each. Translocations t(8;21) and t(15;17) were not detected. Median age of t(7;12)-positive patients was similar to t(7;12)-negative ones (7.0 vs 6.9 mo). All 6 patients with t(7;12) referred to AML high-risk group. Median WBC count was 29.7*109/L (range 15.7-210). Five of 6 patients had initial CNS disease, in all cases extramedullary organ involvement was observed. Three out of 6 t(7;12)-positive patients had immature FAB variants (one AML M0 and 2 AML M1), 2 patients had AML M5a and 1 BAL. Translocation t(7;12) was associated with immature immunophenotype. CD34-positive/CD117-positive cells were revealed in all 6 cases, that was significantly more common in comparison to t(7;12)-negative cases (p=0.004 and p=0.038, respectively). Interestingly, co-expression of CD7 antigen was detected in 5 out of 6 t(7;12)-positive cases and this phenomenon was observed in t(7;12)-positive group more frequent than in t(7;12)-negative ones (p=0.001). In 5 out of 6 cases t(7;12) was cryptic and was not found by CBA. In 5 patients extra copy of chromosome 19 was revealed, that could serve as predictor of presence of t(7;12). Application of 3-color FISH showed 2 types of breakpoint at chromosome 7: in 5 cases breakpoints localized at 7q36; 1 patient had interstitial deletion 7q11q36 and blue fluorescent signal was observed at 7q11. Hematological remission after first induction course was achieved only in one half of t(7;12)-positive patients. Relapses occurred in 3 patients. Hematopoietic stem cell transplantation (HSCT) was performed in 1st remission in 4 cases and 2nd remission in 1 case. EFS and OS were similar in t(7;12)-positive and t(7;12)-negative groups (0.33±0.16 vs 0.39±0.07 p=0.573 and 0.60±0.21 vs 0.45±0.08 p=0.571) with median of follow-up time 29 months.Conclusions. Our results provide additional clinical, immunological and cytogenetic data of t(7;12)-positive patients. Application of novel 3-color FISH approach revealed t(7;12)(q36;p13) in 7.4% infants with AML. Among MLL-negative patients it was the most common cytogenetic aberration (19.4%). Application of HSCT in both 1st and 2nd remission could overcome unfavorable influence of this translocation and led to appropriate OS. DisclosuresNo relevant conflicts of interest to declare.

18F-FDG PET/CT for Staging and Detection of Extramedullary Organ Involvement in Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy characterized by the accumulation of monocytes in the blood and bone marrow, dysplastic hematopoiesis, and potential leukemic involvement of organs. We report a case of leukemic involvement of cervical lymph nodes detected by 18F-FDG PET/CT. A 53-year-old woman with CMML and newly diagnosed cervical lymphadenopathy underwent whole-body PET/CT for evaluation of extramedullary disease. PET demonstrated marked tracer uptake in cervical lymph nodes. Histopathological evaluation revealed leukemic involvement. 18F-FDG PET/CT is a valuable tool enabling sensitive staging of CMML, particularly in case of extramedullary organ involvement.

Cig-FISH-Analysis of Extramedullary Myeloma Manifestations Shows Similar Incidence of Prognostic Genetic Aberrations Compared to Bone Manifestations or Soft Tissue Involvement

AbstractAbstract 4993 Introduction:Extramedullary organ impairment in patients with multiple myeloma (MM) is a very rare event, mostly occurring during disease relapse after high-dose chemotherapy with autologous or allogeneic stem cell transplantation. Recent data reported by different authors suggest a very unfavorable outcome and rapid clinical course for patients with extramedullary relapses. Often the extramedullary manifestations are associated with special biological features, such as loss of CD56 expression or plasmablastic cell morphology.In this context, only one FISH study of 9 MM patients reported that the incidence of TP53 deletions in the bone marrow of those MM patients with central nervous system (CNS) involvement was about 75% higher than in the MM patient without CNS involvement. However, there is a lack of genetic data for specific extramedullary manifestations. We herein report the first cytogenetic investigation of extramedullary organ infiltrations compared to bone lesions or consecutive soft tissue impairment of MM patients using cIg-FISH on paraffine embedded sections. Material and method:We investigated paraffin-embedded sections of different extramedullary organ manifestations of 13 MM patients and 11 MM patients with bone or soft tissue impairment originating from a bone lesion. Extramedullary organ involvements comprised biopsies from skin, pleura, pleural effusion, uterus, liver, CNS, subcutaneous soft tissue, lymph node, and thyroid gland, attained at different stages of the disease. The second group consisted of bone lesions or surrounding soft tissue, like muscle, which was infiltrated per continuitatem. For investigation of paraffine-embedded samples, we further developed the conditions of the well known cIg-FISH method to utilize all the advantages of this very sensitive method. We evaluated the most important prognostic chromosomal regions in MM using the following FISH-probes:13q14 (D13S25), 17p13 (TP53), 8q24 (MYC), t(4;14) (FGFR3/MMSET;IGH). Results:The incidences in the group of extramedullary organ involvement vs. bone and soft tissue were as follows:deletion of TP53: 23% vs. 18%MYC-overrepresentation: 36% vs. 36%deletion of 13q14: 18% vs. 36%t(4;14) 42% vs. 30%The incidence of TP53 deletions in organ infiltrations by malignant plasma cells was similar to bone or soft tissue involvement. Our result for MYC-overrepresentation is in line with the findings of recent analysis of bone marrow aspirates from patients with advanced multiple myeloma (32%) and showed again no difference between the two groups. Incidences of 13q14 deletion and t(4;14) varied slightly between the two groups, but are in range with other cIg-FISH-analyses on bone marrow plasma cells. Discussion:In this first cytogenetic investigation of extramedullary manifestations in MM patients, we showed similar frequencies of the chromosomal regions analyzed in the group of organ infiltrations by malignant plasma cells compared to bone or soft tissue involvement. All in all we could not detect differences in the incidence of the most relevant genetic aberrations of the investigated tissue probes compared to already well known bone marrow cytogenetics. Interestingly, this is in contrast to the findings of bone marrow probes in the study with patients with MM and CNS involvement, who showed a higher incidence of TP53 deletions. Concerning the group of soft tissues, originating from bone lesions this is not astonishing, maybe even expected. However, this work analyzed bone marrow of the MM patients and not the extramedullary manifestation, as we did. Further investigations or larger patient samples are needed to proof if these or other genetic aberrations are associated to the aggressive course of extramedullary manifestations of MM. Disclosures:No relevant conflicts of interest to declare.

High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia.

Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell-derived factor-1 (SDF-1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF-1 (r = 0.73, P = 0.001). Inhibition of SDF-1-induced migration by an anti-CXCR4 monoclonal antibody (78.33 +/- 23.86% inhibition) evidenced the specificity of CXCR4 to SDF-1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66.12 +/- 66.17) than patients without extramedullary organ infiltration (median 17.56 +/- 19.29; P < 0.001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102.74 +/- 92.13; P < 0.003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.

Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia. Associations with hyperleukocytosis and acute monocytic leukemia.

There were 294 children with acute myelogenous leukemia (AML) entered into the German AML Berlin, Frankfurt, and Münster hospitals (BFM) 78 and 83 studies. Thirty (10%) died as a result of hemorrhage and/or leukostasis prior to or in the first 12 days of therapy. The risk of early death due to hemorrhage and/or leukostasis is significantly greater when certain features are initially present: acute monocytic leukemia (French-American-British [FAB] M5), hyperleukocytosis (greater than or equal to 100,000/microliter), and extramedullary organ involvement (P less than 0.001). The risk increases sharply when these factors exist in combination: 72% mortality with FAB M5 and hyperleukocytosis, and 43% with FAB M5 and extramedullary organ involvement. In 11 patients leukostasis alone or in combination with hemorrhage was probably the cause of death during the first 3 days after diagnosis. All 11 children presented with hyperleukocytosis and were classified as monocytic subtype FAB M4 or M5. After induction, a close temporal association between rapid blast reduction and occurrence of fatal hemorrhage was established in five patients. Thrombocytopenic hemorrhages were controllable and, therefore, responsible for death only in exceptional cases. It is difficult to avoid these early fatal complications with current therapeutic measures. Early exchange transfusion together with special supportive care may be useful.