Menke, David M.

e20044 Background: Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg-type (PCDLBCL) is a rare lymphoma comprising 4% of all cutaneous lymphomas with an aggressive clinical course. We investigated disease characteristics and outcomes among patients PCDLBCL. Methods: Following IRB approval, we identified patients retrospectively with PCDLBCL treated at the Mayo Clinic Cancer Center 1998-2019. Results: 45 pts were identified with a median age of 71 years (Range- 48-95) and 28 (62%) were female. Disease locations were legs (62%), arms (22%), head (11%), trunk (2%) and multiple sites (2%). At diagnosis, (51%) had a single lesion, (29%) had multiple lesions in 1-2 contiguous regions, (16%) had multiple lesions in non-contiguous regions or > 2 regions and data was not available (4%). Immunohistochemistry showed positive staining for BCL-2 (92%), BCL-6 (76%), c-MYC (62%), MUM1 (95%), CD10 (11%), and cytoplasmic IgM (8/9- 89%). By Han’s criteria, (95%) had activated B cell lymphoma (ABC). Median Ki-67 was 90% (range, 50,100%). 9/12 (75%) were positive for MYD88 L265P mutation. 13/21 (62%) were double expressor and 3/22 (14%) had double hit lymphoma. 37/45 (82%) had ECOG < 2. LDH was elevated in 13/37 (35%). The median number of therapies was 1 (range; 1-11). The initial treatments were chemo-radiation (30%), chemo alone (38%), rituximab alone (11%), radiation (RT) alone (16%), rituximab-RT (2.5%), and surgical (2.5%). The median follow-up time for the whole cohort was 80 months (95% CI; 32, 169). The median progression free survival and overall survival (OS) were 20 months (95% CI; 12, 34) and 80 months (95% CI; 48, 119). 22/45 (49%) are alive. The cause of death was disease-related in 11/23 (48%). The median number of relapses was 1 (range; 0, 11) with (60%) relapsed after first line. 4/45 pts had autologous stem cell transplant after relapse. 7/45 (16%) had a systemic relapse at a median time of 35 months from diagnosis (range; 16, 112). Age above 60 years was associated with worse OS; 70 months (95% CI; 30, 99) vs NR (95% CI; 135, NR), p = 0.025. ECOG performance status < 2 was associated with better OS, NR months (95% CI; 80, NR) vs 48 months (95% CI; 3.3, 88),p = 0.0003. 1 pt received Ibrutinib on 11th relapse and had 3 years of PFS. Conclusions: PCDLBCL is predominantly ABC type, affects elderly pts and is characterized by multiple cutaneous relapses followed in some cases by systemic relapses. Increased age and poor performance status had a negative impact on OS. High incidence of MYD88 L265P mutation is observed in PCDLBCL similar to immune-privileged site lymphomas.

e20036 Background: Hepatosplenic T cell lymphoma (HSTL) is a rare subtype of mature T cell lymphomas accounting for less than 1 percent of non-Hodgkin lymphomas. it has been associated with poor prognosis. It typically involves sinusoids in the spleen, liver, and bone marrow. Methods: Following IRB approval, we retrospectively evaluated patients with HSTL treated at the Mayo Clinic Cancer Center 1996-2019. Kaplan-Meier survival analysis and univariate analysis to identify prognostic factors were performed. We investigated clinical characteristics and outcomes among patients with HSTL. Results: 22 patients (15 males) with median age of 45.5 years (range- 15.5-80.6) were identified. The majority of patients had B symptoms (12/22), cyotpenias (20/22), massive splenomegaly (16/22), liver involvement (13/22), and/or bone marrow involvement (14/22). Additionally, 42% tested positive for peripheral blood involvement and 8/22 (36%) were on chronic immunosuppression related to solid organ transplant (2), inflammatory bowel disease (2), and rheumatologic disorders (4). Phenotypically, the majority of patients were positive for gamma/delta (18/22), isochromosome 7q (8/13), and 4/9 (44%) tested positive for trisomy 8. Initial therapies included CHOP/CHOEP (14), ICE (2), EPOCH (1), pentostatin (1), and radiation (1). The median follow-up was 33 months (range 2,137). Progression free survival and overall survival (OS) were 9.5 months (95% CI; 1.8, 16.3) and 12 months (95% CI; 4.9, 18.5) respectively. 10/22 (45%) underwent splenectomy with one patient receiving splenectomy alone as treatment. 8/22 (36%) had stem cell transplant (SCT- 5 allogeneic and 3 autologous). Out of the 22 patients 4 (18%) were long-term survivors with 55, 74, 95, and 137 months; 3/4 had splenectomy at diagnosis and 2/4 had allogeneic SCT. The longest survivor had splenectomy only. Liver involvement was associated with worse OS; 10 months (95% CI; 1.6, 18) vs 35 months (95% CI; 4, NR), p = 0.036. Immune suppression at diagnosis was associated with worse OS; 5 months (95% CI; 1.3, 18) vs 18 months (95% CI; 9, 74), p = 0.036. A trend for better OS was seen with splenectomy and SCT. Conclusions: HSTL is a rare lymphoma with poor prognosis. Long-term survival was seen in 18% only. Liver involvement and immune suppression had a negative impact on OS. A larger cohort is needed to better evaluate the impact of different treatment options.

Abstract Most common abnormalities in MDS involve the loss of chromosomal material resulting from the loss of an entire chromosome or a part of it, due to deletions or unbalanced translocations. Among partial chromosome losses, del (5q) was found to be the most common followed by del (20q). MDS can also be associated with multiple morphologic RBC abnormalities including macrocytes, ovalocytes, dacrocytes, fragmented cells and basophilic stippling. Limited cases of MDS with elliptocytosis have been reported in the literature. Elliptocytosis encompasses a heterogeneous group of erythrocyte disorders. Although acquired cases of elliptocytosis have been reported, these are most often hereditary disorders with a variable clinical presentation from asymptomatic carriers to patients with severe hemolytic anemia. This disorder is quite rare in the Unites States (US). Mutations in protein 4.1, alpha spectrin, beta spectrin, glycophorin C and band 3 have been reported in hereditary elliptocytosis. Only 7 well reported cases of marked elliptocytosis associated with MDS have been reported in the literature. Of those 7 cases, 4 of them were associated to del(20q). All of them were elderly males and all of them had ≤ 5% bone marrow blasts. Anemia is usually moderate (median 9.4 g/dL; range 8.1–12) and thrombocytopenia is mild to moderate (median platelet count 116 x 109/L; range 46–149 x 109/L). All cases were described either in Europe (n= 1; Rummens et al. Acta Haematologica1986; 75:174–177) or in Asia (n= 3; Ideguchi et al. Br J Haematol.1993, 75:387–92; Ishida et al. Cancer Genetics and Cytogenetics1997, 108:162–165; Hur et al. Clin Lab Haematology, 2004, 26: 69–72). Of these 7 cases, 3 of them were associated with protein 4.1 deficiency. To the best of our knowledge these are the first 2 cases of patients with marked elliptocytosis and MDS with del 20q abnormality reported in the US: Patient 1 Patient 2 Age/sex 82/male 79/male FAB classification RA RA Year of diagnosis of MDS 1998 1999 WBC 3.0 x 109/L 11.5 x 109/L Platelets 82 x 109/L 79 x 109/L Hemoglobin 11.8 g/dL 10.7 g/dL Hematocrit 34.4% 31.9% Reticulocyte 4.3% NA LDH 350 u/L NA Direct Coombs Negative NA BM Cytogenetics 46 XY, del (20)(q11.2) 46 XY, del (20)(q11.2) Prior Therapy supportive care only Erythropoeitin Evaluation for protein 4.1 deficiency in one of these 2 patients is currently pending. The elliptocytosis noted in these MDS patients were most likely derived from acquired clones with abnormal development of the erythroid lineage and were associated with deletion of chromosome 20q. Patients with acquired elliptocytosis and associated MDS with del 20q chromosomal abnormality seem to have an indolent course with prolonged history of mild to moderate blood cytopenias and low risk to transformation to acute leukemia. Further research is needed to deduce the clinical significance of this subtype of MDS with this unusual RBC morphology

Abstract Background: Castleman Disease (angiofollicular hyperplasia) is a rare, lymphoproliferative disease. There has been no large study describing the natural history of this disease. Hypothesis: A retrospective analysis of clinical, pathologic, and laboratory factors predictive of outcome should be identifiable. Methods: During the period from 3/30/48 to 6/18/2002, 114 patients with Castleman Disease were seen at the Mayo Clinic (Rochester, 56; Jacksonville, 19; Arizona, 13) and at the University of Nebraska (26). Pathology, laboratory and clinical characteristics analyzed included: the presence of unicentric or multicentric disease, the pathologic variant (hyaline vascular versus plasma cell variant), co-existing POEMS syndrome, age, serum albumin, alkaline phosphatase, AST, sedimentation rate, the presence of cytopenias, organomegaly (hepatomegaly or splenomegaly), papilledema, peripheral neuropathy, sclerotic bone lesions, renal disease, B-symptoms or respiratory symptoms. The impact of these variables on overall survival from time of diagnosis was evaluated using univariate analyses, where their significance was determined based on the logrank statistic. To derive the multivariable model, the score-based model-building method was used. Based on this approach, a 3-variable model was designed, adjusting for age at diagnosis. Patients were then assigned a risk score corresponding to how many of these risk factors they possessed. A final proportional hazards model was constructed based on this risk score. Results: The median age at diagnosis was 43 (range: 5 – 78), and 48% of patients were male. Fifty-five patients had multicentric disease. Median follow-up of living patients was 5.8 years (range: 0.02 – 27). On univariate analysis, factors that predicted for overall survival included: age at diagnosis, presence of multicentric disease, presence of a monoclonal protein in the urine, co-existing POEMS syndrome, serum albumin, presence of cytopenias, organomegaly, neuropathy, thrombocytosis, and respiratory symptoms. The final multivariable model included 98 patients. Adjusting for age, the model included organomegaly, respiratory symptoms, and thrombocytosis. Patients were assigned 1 point for each risk factor they possessed based on clinical relevance and similarity of the hazard ratios for each of these 3 variables (ranging from 3.1 to 4). A final prognostic survival model was constructed using this assigned risk score. These scores were collapsed further based on observed similarities (0 factors vs. 1 or more factors). This final model yielded a hazards ratio of 5.5 (95% CI 2.3–13.4). The 10 year survival rates were 80% (95% CI: 65–98%) and 41% (95% CI: 28–59%) for the 0 factor and 1+ factor groups, respectively. The 20 year survival rates were 71% (95% CI: 52–87%) and 31% (95% CI: 19–51%), respectively. Conclusion: The most distinguishing prognostic clinical, laboratory, and pathological characteristics of Castleman’s Disease are orgnaomegaly, respiratory symptoms, and thrombocytosis. This prognostic scoring system should aid in individual cases and in assessing results of therapeutic interventions.

Abstract Background: IgM multiple myeloma (MM) are very rare plasmaproliferative disorders representing 0.5–1.2% of all cases of MM and &lt; 0.2% of all IgM monoclonal gammopathies. Clinical criterion are not always helpful in differentiating IgM MM from Waldenstrom macroglobulinemia. However, the presence of lytic bone lesions, absence of lymphadenopathy and/or hepatosplenomegaly, presence of translocation of the immunoglobulin heavy chain locus at 14q32 [t(11;14), t(14;16), t(4;14)], and strong expression of CD138 by the plasma cells are useful in the diagnosis of IgM MM. It has been our experience and of others that these cases have an aggressive behavior at presentation, shorter survival than IgG and IgA MM and poor response to therapy for lymphoplasmacytoid lymphomas. We present here 2 cases of IgM MM with a dramatic response to Lenalidomide and low dose dexamethasone (Rev/Dex) Results: Baseline patient characteristics at time of diagnosis of IgM MM and therapy outcome are presented in the following 2 tables: Table 1. Case 1 2 Age and sex 72 (F) 73 (F) Serum M-spike (g/dL) 5.3 6.2 Urine M-spike (mg/dl/24 hrs) 72 412 Serum IgM (mg/dL) 8,590 11,000 BM plasma cells percentage 90 20 Plasma cell immunophenotyping CD138+++, partial CD20, CD56− CD138+++, partial CD20, CD56− Cytogenetics (Standard and/or FISH) Standard: normal FISH: not done on initial biopsy. On follow up there were insufficient number of plasma cells to perform test Standard: of 20 metaphases, 6 had a complex hypotetraploid karyotype with relative loss of 13q, 14, 15, 16, 20, and 22, and numerous unbalanced rearrangements. FISH: a plasma cell clone with monosomy 13 and IGH/c-MAF fusion, t(14;16). In addition, approximately 60% of plasma cells had a tetraploid clone with the same anomalies as well as relative loss of p53 Bone lesions Multiple non-traumatic spinal fractures and of stenum Several lytic lesions of long bones Renal insufficiency No No Anemia (Hbg g/dL) Yes (8.7) Yes (8.1) Hypercalcemia (Ca mg/dL) Yes (12.5) Yes (11.4) Beta 2 microglobulin (mg/dL) 5.79 8.51 Serum viscosity (cpoise) 5.9 4.8 Table 2. Best Response to therapy Case Therapy Best Response Comments 1 Rituxan, then Fludarabine based therapy Transient response Rapid progression after partial and transient response to each therapy 1 Lenalidomide + LD-Dex sCR after cycle #6. Currently on CR 18 months later IgM declined from 8,590 to 43 mg/dL after 4 cycles of Rev/Dex. 2 Lenalidomide + LD-Dex VGPR after cycle #2 IgM declined from 11,000 to 463 mg/dL after cycle 3. Complete disappearance of M-spike in serum; BM to be done after cycle #4 Conclusions: This is the first report that we are aware of a rapid and dramatic response to lenalidomide and low dose dexamethasone in these rare cases of IgM MM with poor response to NHL-type treatment. Lenalidomide-based therapy might abrogate poor prognosis cytogenetics in this unusual subtype of MM (case #2), however, follow up for this patient is still very short.

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.

Otolaryngologists are called upon to evaluate and treat sinonasal masses discovered incidentally on imaging studies. Although common conditions such as sinonasal polyps and mucus retention cysts predominate, it is prudent practice to formulate a differential diagnosis to identify unusual conditions. We present a case of a maxillary sinus mass in a 78-year-old man that was discovered incidentally on brain imaging and subsequently identified on biopsy as an angiomyolipoma (AML). AMLs are benign hamartomatous tumors that rarely occur in extrarenal locations. Only a few cases have been reported in the nasal cavity. We believe our case represents the first reported instance of AML arising within a maxillary sinus. Identification of intratumoral fat within the mass on imaging studies may suggest the diagnosis of AML preoperatively. Close interdisciplinary collaboration among the otorhinolaryngology, radiology, and pathology services is beneficial for patient management. We report this case to raise awareness that AML can arise in this previously unreported location. Moreover, we wish to emphasize that AML should be considered in the differential diagnosis when imaging studies demonstrate a well-defined, heterogeneous, fat-containing solitary mass in the nasal cavity or maxillary sinus.

7516 Background: PCNSL is a diffuse large B cell lymphoma confined to the CNS. Pomalidomide (POM) is a novel immunomodulatory agent with excellent CNS penetration (~40%) based on CNS PK analysis in rats and pre-clinical therapeutic activity against CNS lymphoma. Methods: A Phase I clinical trial was undertaken to determine the maximal tolerated dose (MTD) of POM, safety profile and overall response rate (ORR). Treatment consists of POM daily for 21 days every 28 days in combination with dexamethasone 40 mg PO weekly for two cycles followed by POM alone in subsequent cycles until progression or intolerance. 4 dose escalation levels of POM (3mg, 5mg, 7mg, and 10 mg) were planned. Thromboprophylaxis with oral anticoagulant or aspirin was required. MTD determination has been completed and expansion of the MTD cohort is ongoing. Therapeutic responses were evaluated per the international PCNSL collaborative group (IPCG) criteria after 2 cycles of treatment. The trial is registered with ClinicalTrials.gov (#NCT01722305). Results: 21 of 25 patients accrued were eligible for assessment. The MTD was determined to be 5 mg qd for 21 days every 28 days. Two DLTs were seen at dose level 3 (Grade 3 dyspnea and grade 4 thrombocytopenia). One DLT was seen in the expanded MTD cohort (Grade 4 neutropenia and lymphocytopenia). ORR for the study (9/21) was 43% (95% CI- 22%, 66%) with 4 CR, 1 CRu and 4 PR. 3 responders completed 2, 4, and 6 cycles before progression. 6 responders have completed 4, 5, 6, 10, 12, and 32 cycles and remain on treatment. ORR for the MTD dose level was (5/12) 42% (95% CI- 15%, 72%) with 3 CR and 2 PR. 2 patients had stable disease (SD). Pseudo-progression was seen in 1 patient. Overall, grade 3/4 toxicity was hematologic (neutropenia, anemia, and thrombocytopenia) in 38.1% and non-hematologic in 33.3% (fatigue, pneumonia, sepsis, syncope, dyspnea, hypoxia, respiratory failure and maculo-papular rash). Percent CSF/blood ratio of POM was determined to be 19% in 1 patient. Conclusions: Pomalidomide treatment is feasible with therapeutic activity against relapsed/refractory PCNSL and should be further developed. Clinical trial information: NCT01722305.