Extensive Bone Marrow Involvement Research Articles

Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone followed by brentuximab vedotin consolidation in CD30-positive peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 study

CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes. We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort. 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths. In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active. SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health.

Efficacy and Safty of Stem Cell Mobilization with Etoposide +Cytarabine Plus G-CSF in Patients with Lymphoma at High-Risk of Mobilizing Failure

Objective：Sufficient peripheral blood stem cell (PBSC) mobilization is important for performing successful autologous stem cell transplantation (ASCT) in patients with lymphoma. However, the optimal mobilization strategy remains a matter of debate in lymphoma.The aim of the study was to explore efficacy and safety of PBSC mobilization using etoposide combined with Cytarabine (EA) plus G-CSF in patients with lymphoma at high-risk of mobilizing failure. Methods：This retrospective study explored efficacy and safety of PBSC mobilization using EA (etoposide 50~100 mg/m2 , qd d1~3; AraC 0.5 g/m2 , q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 81 patients with lymphoma at high-risk of mobilizing failure. As previously reported, patients were defined at high-risk of mobilizing failure if (i) previous collection attempts failed (no special instructions); (ii) previous extensive radiotherapy or a complete course of treatment had affected stem cell activity; or (iii) any of these conditions: advanced disease (2 lines of chemotherapy), refractory disease, extensive bone marrow involvement or cellularity &amp;lt;30% at the time of mobilization or age 65 years. Results：The mean total and first apheresis trial CD34+ cells collection was 20.37(range 1.08~138.96) and 18.56(range 0.1~138.96)×10^6 CD34+ cells/kg, respectively. Overall, 79(97.5%) patents harvested adequate mobilization (≥2×10^6 CD34+ cells/kg), while 65(80.2%) patients achieved optimal mobilization(≥5×10^6 CD34+ cells/kg). A single apheresis was sufficient to reached the target yield of adequate apheresis in 67(82.7%) patients on median 15th day (range 11~19). We observed acceptable hematological toxicity and exposure of antibiotic usage in 57 patients with a median of 4 days. No severe infections or mobilization-related mortality were observed. Conclusion：Our resluts suggest that EA plus G-CSF is an effective and safe PBSC mobilization strategy for patients with lymphoma, including those predicted as poor mobilizers. The outcome should be evaluated in a randomized study.

Genetic Basis of Relapse after GPRC5D-Targeted CAR T Cells

GPRC5D-targeted CAR T cell therapy was recently shown to be safe and active in patients with relapsed or refractory multiple myeloma with limited or no other therapeutic options, such as those with triple-refractory disease (to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody) and disease progression on a BCMA antibody-drug conjugate, bi-specific T-cell engager, and/or CAR T cell therapy (Mailankody S. et al. NEJM 2022). Among the 17 patients treated in our phase 1 study of the GPRC5D-targeted CAR T cell therapy MCARH109, 12 patients had an objective response and 6 patients relapsed after an initial response of 3-9 months. While there are currently no validated clinical assays to assess GPRC5D expression, we reported decreased or loss of protein expression using immunohistochemistry in all 6 patients who relapsed. This finding suggests that genetic alterations may be an important mechanism of antigen escape after GPRC5D-directed CAR T cell therapy. With BCMA-directed CAR T cell therapies recently approved for multiple myeloma, antigen loss due to genetic alterations is a rare mechanism of resistance. We first investigated the genetic status of GPRC5D in a patient (Patient 15) who underwent biopsies of a left posterior chest wall plasmacytoma at baseline and a recurrent plasmacytoma at the same site at relapse with nearly 100% tumor. This patient received the maximum tolerated dose of 150×10 6 GPRC5D-directed CAR T cells and achieved a best response of stringent complete response without minimal residual disease in the bone marrow. Unfortunately, 6 months after infusion, he relapsed with recurrent FDG-avid lesions in similar locations on PET, extensive bone marrow involvement (90-95%), rapidly rising lambda free light chain in the serum, and significantly decreased but still detectable circulating CAR T cells (CAR vector copies per mL: 666) ( Figure A). We performed droplet digital PCR (ddPCR) on extracted DNA from the plasmacytoma biopsies and estimated GPRC5D copy number to be two at baseline and 0.1 at relapse, consistent with bi-allelic loss in a significant majority of plasma cells. We then performed whole exome sequencing which revealed two balanced copies of GPRC5D at baseline and bi-allelic loss at relapse consisting of a broader deletion (~8756 kb) in chromosome 12p in one allele and a more focal deletion (~145 kb) encompassing the GPRC5D gene locus in the second allele ( Figure B). Beyond this patient, we identified that relapses after GPRC5D-directed CAR T cell therapy are associated with decreased or loss of GPRC5D mRNA expression. We measured GPRC5D mRNA expression by ddPCR on patient bone marrow or plasmacytoma samples at baseline prior to CAR T cell infusion and at disease progression. The results corresponded with those from immunohistochemistry, and all patients who relapsed showed reduced or absent GPRC5D mRNA and protein expression at disease progression. Given that two patients who responded and relapsed had low or no GPRC5D expression at baseline (Patients 10 and 13), further studies are warranted to characterize the heterogeneity of GPRC5D expression and how well immunohistochemistry and ddPCR capture its expression. Here we report that antigen escape after GPRC5D-directed CAR T cell therapy can be mediated by structural chromosome alterations resulting in bi-allelic loss of the GPRC5D gene locus in a patient with initial excellent response. We also note transcriptional downregulation of GPRC5D in other patients at relapse, but it remains to be determined whether this is transient or durable and whether it can be explained by similar on-target genetic alterations or non-genetic mechanisms. Our patients with heavily pretreated multiple myeloma may harbor greater tumor heterogeneity and genomic instability than previously described, which can facilitate clonal outgrowth of antigen-negative tumor cells under continuous selective pressure of GPRCRD-targeted CAR T cells. Potential strategies to mitigate antigen escape-mediated relapse in myeloma patients receiving T-cell engaging therapies including earlier use of these therapies, multi-antigen targeting, or combination approaches are being evaluated in ongoing trials.

Alveolar rhabdomyosarcoma with multiple bone marrow infiltration

A 15-year-old girl visited Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University, Changsha, China) in November, 2022, because of a 13-day history of lower back and leg pain. She had no previous medical history. Her symptoms did not alleviate after treatment with intravenous fluids and analgesics in a local hospital. Abdominal tenderness and muscle spasm were detected on physical examination. Laboratory test results showed a white blood cell count of 14·03 × 109 per L (reference range 4–10 × 109 per L), a neutrophil count of 9·6 × 109 per L (reference range 1·3–8·3 × 109 per L), a monocyte count of 0·78 × 109 per L (reference range 0·14–0·6 × 109 per L), and a platelet count of 85 × 109 per L (reference range 100–300 × 109 per L). PET-CT scan showed extensive and diffuse bone marrow involvement and a hypermetabolic subcutaneous nodule in the chest wall (figure). Therefore, lymphoma was considered as the initial diagnosis.

Salvage Radioligand Therapy with Repeated Cycles of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer with Diffuse Bone Marrow Involvement

Simple SummaryMetastatic castration-resistant prostate cancer (mCRPC) with extensive spread to the bone marrow is an incurable stage of disease associated with a poor prognosis and a high risk of impaired blood cell formation. Therapeutic options prolonging survival are limited and may result in significant bone marrow toxicity. The concept of radioligand therapy (RLT) in mCRPC is marked by the targeted delivery of radionuclides, such as beta particle emitting 177Lutetium (177Lu) to the prostate-specific membrane antigen (PSMA), a transmembrane protein frequently present on prostate cancer cells. RLT has yielded promising anti-tumoral activity and excellent tolerability in patients with mCRPC as shown by multiple retrospective series and a growing number of prospective trials. The presented study aims to investigate the role of RLT in mCRPC patients with metastases diffusely involving the bone marrow. Special emphasis is laid on identifying early indicators for a favorable treatment response and potential risk factors for adverse outcomes. The impact of RLT-specific variables, including administered treatment activity, cumulative activity and whole-body absorbed dose is assessed individually.Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with 177Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq 177Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0–9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2–12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18–8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000–1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with 177Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.

Abstract 1114: Role of the FGFR1-KDM2B-EZH2 signaling axis in bone-marrow microenvironment mediated tumor survival &amp; drug resistance in Mantle cell lymphoma

Abstract Mantle Cell Lymphoma (MCL) is a rare but aggressive form of Non-Hodgkin's lymphoma, with high rates of progression &amp; extensive bone marrow (BM) involvement. There is a high propensity towards development of drug resistance against treatment options presently available such as ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor. The BM provides a secure niche for MCL cells to thrive. Unbiased transcriptome analysis revealed Fibroblast Growth Factor Receptor-1 (FGFR1) as a major upregulated candidate in ibrutinib-resistant (IR) patients &amp; MCL cells cultured under the influence of BM stroma. FGFR1 knockdown downregulates expression of EZH2 (a catalytic subunit of PRC2 complex involved in epigenetic regulation), which has a high expression in BM stroma cultured MCL cells &amp; linked to poor patient survival. A putative protein linking these two is KDM2B (Lysine demethylase 2B) shown in other cancer types. We found KDM2B to be higher in BM stroma cultured MCL. However, there is no known information regarding presence/functioning of the FGFR1-KDM2B-EZH2 axis, along with if/how this axis may confer stroma-mediated proliferative or drug resistance benefits in MCL. In this study, we performed variety of proliferation, ibrutinib sensitivity &amp; cell survival tests on MCL grown under BM stromal influence. Cytokine arrays were performed to identify specific cytokine upregulation in stromal milieu, followed by subsequent stromal knockdown &amp; reevaluation of MCL growth kinetics. FGFR1 &amp; KDM2B were individually knocked down (KD) in IR-MCL cells &amp; above-mentioned assays repeated. ChIP-qPCR studies for binding to promoter of miR-101, a previously identified negative regulator of EZH2, were also performed. Our results show that ibrutinib-sensitive MCL patient derived cells have greater proliferation &amp; decreased ibrutinib sensitivity when grown under BM stromal influence, &amp; higher expression of FGFR1, KDM2B &amp; EZH2. The stroma-induced growth advantage is reversed when FGFR1 inhibitor is supplemented in the stromal milieu. Cytokine array identified IL-6 as a major upregulated cytokine in BM stroma-conditioned media, with IL-6 seen to enhance FGFR1 expression &amp; IL-6 KD in stroma reversing the MCL growth advantage. KD of FGFR1 &amp; KDM2B individually in MCL-IR cells reduced proliferation &amp; increased sensitivity to ibrutinib. KDM2B &amp; EZH2 expression were lowered in FGFR1KD cells &amp; expression of miR-101 was increased, along with decreased fold enrichment of KDM2B at the miR-101 promoter locus, indicating a decreased KDM2B-mediated repression of this negative regulator of EZH2, a possible reason for EZH2 down-regulation. These results indicate the vitality of FGFR1-KDM2B-EZH2 signaling axis in tumor progression &amp; drug resistance, shedding light on mechanisms for BM microenvironment mediated tumor survival, paving way for identification of new druggable targets. Citation Format: Anuvrat Sircar, Satishkumar Singh, Georgios Laliotis, Evangelia Chavdoula, Amber Hart, Philip N. Tsichlis, Lalit Sehgal. Role of the FGFR1-KDM2B-EZH2 signaling axis in bone-marrow microenvironment mediated tumor survival &amp; drug resistance in Mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1114.

Systematic KIT Sequencing Identifies Unsuspected Systemic Mastocytosis with Associated Hematological Neoplasm

Background: Systemic mastocytosis (SM) can occur on its own or in association with non-mast cell disorders (SM with associated hematological neoplasm, SM-AHN). Because extensive bone marrow involvement by non-mast cell disease may obscure mast cells in routinely-stained biopsies, it is possible that SM-AHN is under-recognized. Given the high association between KIT D816V mutations and SM, we asked if systematic evaluation for somatic KIT mutations in patients with known or suspected hematologic malignancies could identify unsuspected cases of SM-AHN.Methods: We queried 5754 clinical next generation sequencing (NGS) samples from 4173 unique patients with known/suspected hematologic neoplasms evaluated at our institution between 1/1/15 and 6/30/17 using a custom, 95-gene, amplicon-based NGS panel (PMID 27339098). Exons 8-9, 11 and 17 of KIT were analyzed. In patients with a somatic KIT mutation but without known SM, marrows were assessed for SM with mast cell tryptase and CD25 immunohistochemistry (IHC).Results: We identified 37 somatic KIT mutations in 35 patients (Figure), including non-D816V (n=9) and D816V (n=26; 1 case with concurrent D816Y).Non-D816V KIT mutations occurred in 9 patients: 5 core-binding factor-rearranged acute myeloid leukemia (CBF-AML) [418_419insFF (n=1); 417_419TYDdelinsI (n=1); Y823C (n=1); D816Y (n=2; 1 with also V559D)], 1 AML with myelodysplasia-related changes (AML-MRC; 419delD), 1 acute promyelocytic leukemia (N822K), 1 chronic myelomonocytic leukemia (R634W), and 1 mast cell leukemia (D816Y). In addition to the patient with mast cell leukemia, 2 patients with CBF-AML had known SM [418_419insFF; D816Y and concurrent V559D]. IHC performed for this study on the remaining 6 cases did not reveal multifocal, dense aggregates of abnormal mast cells.Of the 26 cases with the D816V variant, 18 had an established diagnosis of SM [SM without AHN (n=6); SM with suspected AHN, based on marrow morphology and/or abnormal peripheral counts (n=5); SM-AHN where AHN = chronic myelomonocytic leukemia (n=6) or myelodysplastic syndrome (n=1)]. In the 3 remaining cases of CMML or MDS with KIT D816V (marked on Figure), SM was not clinically or pathologically suspected. IHC performed following identification of the KIT D816V mutation by NGS revealed clusters of spindled, CD25+ mast cells, consistent with SM-AHN. All 3 patients also had a serum tryptase >20 ng/mL and splenomegaly, although these parameters may be influenced by the AHN. In 1 patient, retrospective review of prior liver/lymph node biopsies revealed previously unrecognized aggregates of spindled, CD25+ mast cells accounting for unexplained fibrosis. The patient was started on Midostaurin following SM diagnosis with significant clinical response. The final 5 cases with the D816V variant were AML. This included 4 de novo or therapy-related AMLs in which the KIT mutation was not present at initial diagnosis. In 2 cases, the mutation appeared in peripheral blood at time of relapse after stem cell transplant (concurrent bone marrow biopsy not performed; pre-transplant marrows showed no evidence of SM by IHC). In the other 2 cases, there was no IHC evidence of SM in leukemic marrows bearing the KIT D816V mutation. The final AML was AML-MRC with known KIT mutation; increased, CD25+ mast cells were present at time of AML but were not spindled or clustered.None of the cases of isolated SM had additional driver mutations, whereas 15 of 16 cases of known or suspected SM-AHN exhibited driver mutations in genes that are recurrently mutated in myeloid neoplasms. In the SH-AHN cases, the KIT D816V variant allele fraction varied from subclonal to equivalent to levels of other driver mutations. A group of 30 cases of CMML (n=15) and MDS (n=15) without KIT mutations were used as controls. None of these cases showed IHC evidence of SM.Conclusion: We find that detection of the KIT D816V mutation in CMML or MDS is invariably associated with SM, even in cases in which SM is not clinically suspected. Our data strongly suggest that identification of the KIT D816V mutation in patients with a diagnosis of CMML or MDS should prompt additional testing for underlying SM given the potential prognostic and therapeutic implications. [Display omitted] DisclosuresAster:Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees. Steensma:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Incyte: Equity Ownership; Onconova: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Takeda: Consultancy; H3 Biosciences: Consultancy. Lindsley:Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; MedImmune: Research Funding. DeAngelo:Celgene: Research Funding; ARIAD: Consultancy, Research Funding; Glycomimetics: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Immunogen: Honoraria, Research Funding; BMS: Consultancy; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding.

Molecular Subtypes of Plasma Cell Neoplasms with Circulating Neoplastic Plasma Cells

Background:Circulating neoplastic plasma cells (CNPCs) are frequently seen in plasma cell neoplasms (PCN). Prior studies have shown that CNPCs are usually associated with a higher tumor burden and disease progression. Additionally the percentage of CNPCs in newly diagnosed PCN as quantified by flow cytometric analysis is found to be an independent predictor of survival.The UAMS myeloma group has established a molecular classification of PCNs based on unsupervised hierarchical clustering of gene expression profiling (GEP) data, and has identified 7 subgroups: Hyperdiploidy (HY), Cyclin D-1 (CD-1), CD-2, Low Bone (LB), Proliferation (PR), MMSET/FGFR3 (MS) and MAF (MF). This molecular subtyping in conjunction with the UAMS GEP 70 gene signature profile has been found to be clinically useful in identifying low risk group with superior event-free and overall survival from high-risk group.The purpose of this study was to determine if a particular PCN molecular subtype was more likely to be associated with CNPCs. To the best of our knowledge, the association between the different molecular subtypes and CNPCs has not been studied before.Design:A retrospective review was performed to determine the number of PCN patients with CNPCs during 2015-2016. Peripheral blood immunophenotyping was performed using 8-color multi-parameter flow cytometry analysis. PCN molecular subtypes and GEP risk stratification was performed on CD138-enriched plasma cells from bone marrow aspirate based on our previously established protocol. Additional data including clinical classification, bone marrow plasma cell tumor burden and karyotype analysis were also collected.Results:A total of 305 patient had peripheral blood flow cytometric analysis performed during the study period; 147 patients showed presence of CNPCs (48.19%). Only 120 of the 147 cases with CNPCs had all the additional data and were included for further analysis.Based on UAMS GEP 70 signature risk score, 86 patients (71.7%) showed low risk gene classification compared to 34 patients (28.3%) with high risk gene classification. Distribution of molecular subgroups defined by GEP data, identified that the HY group was the largest subgroup (n=29, 24.2%), followed by CD-2 (n= 24, 20%), PR (n=19, 15.8%), MF (n=15, 12.5%), MS (n=12, 10%), CD-1 (n=12, 10%) and LB (n=9, 7.5%). However, further analysis of low risk group patients identified equal distribution of HY (n=24) and CD-2 (n=23) subgroups. Further analysis of molecular subgroups based on bone marrow tumor burden is listed in Table 1.Based on the international myeloma working group diagnostic criteria, most patients had multiple myeloma (MM) (n=112, 93.3%); smoldering myeloma (n=5, 4.2%) and MGUS (n=3, 2.5%) was less common. Of the MM group, two patients met the criteria for plasma cell leukemia and showed extensive bone marrow involvement. Bone marrow involvement in a cases ranged from <5% to 95% plasma cells; with most patients (72.5%) showing <60% cellularity replacement by plasma cells. Cytogenetic analysis revealed abnormal/complex karyotype in the majority of the patients (n=89, 73%) compared to normal karyotype (n=31, 26%).Conclusions:Our study indicates that CNPCs occurs more frequently in patients with low risk multiple myeloma based on UAMS GEP 70 signature classification especially CD-2 and Hyperdipoidy (HY) subtypes. This correlation is best observed in cases with <60% bone marrow tumor burden. These patients are also more likely to have abnormal/complex karyotype. Further long-term studies should be performed to determine the prognostic significance of these findings. [Display omitted] DisclosuresMorgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria. Davies:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Burkitt lymphoma/leukemia initially presenting with extensive peripheral blood and/or bone marrow involvement: A report of 11 cases from a single institution

Burkitt lymphoma/leukemia initially presenting with extensive peripheral blood and/or bone marrow involvement: A report of 11 cases from a single institution

Brentuximab vedotin for refractory anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in leukemic phase with RUNX3 overexpression.

Anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL) is an aggressive CD30-positive non- Hodgkin lymphoma. ALK-ALCL rarely manifests with extensive bone marrow and peripheral blood involvement (known as “leukemic phase”). A 54-year-old woman was diagnosed with ALK-ALCL in leukemic phase, characterized by an extremely poor prognosis. Lymphoma cells in this case showed chromosomal translocation 1p36.1- encoded RUNX3 and overexpression of its protein. She was refractory to CHOP and salvage chemotherapy. Fortunately, she achieved complete remission with three cycles of Brentuximab vedotin (BV) and underwent umbilical cord blood transplantation. However, she died due to treatment-related mortality on day 129. The autopsy findings showed no lymphoma cells. Treatment strategy for ALK-ALCL is controversial, but the efficacy of BV in CD30-positive peripheral T-cell lymphoma not only as salvage regimens, but also in first line, has been reported in recent years. BV may be an effective option for ALK-ALCL in leukemic phase.

Leukemic phase of Richter transformation: A mimic of acute myeloid leukemia that responded to Ibrutinib monotherapy.

Here we report an unusual case of RT without any clinical, laboratory, or radiologic evidence suggestive of transformation other than cytopenia. Without any significant extramedullary involvement, RT presented in a leukemic phase that mimicked acute myeloid leukemia (AML). Importantly, despite the presence of a number of risk factors associated with a poor outcome, such as clonal relatedness, complex karyotype, expression of CD38 and ZAP70, thrombocytopenia, and multiple prior therapies, the patient responded well to ibrutinib monotherapy. This article is protected by copyright. All rights reserved.

Disseminated Cryptococcosis in a Young Immunocompetent Male

Cryptococcosis is an opportunistic infection caused by encapsulated yeasts of genus Cryptococcus. It usually infects immunocompromised patients and has multisystemic involvement, the common sites being lungs, central nervous system, skin and bone marrow. Disseminated cryptococcosis has also been reported in immunocompetent individuals. We present an immunocompetent patient with disseminated cryptococcosis and extensive bone marrow involvement.

A Multicenter Study of Romiplostim to Treat Chemotherapy-Induced Thrombocytopenia in Solid Tumors and Lymphoid Malignancies

Introduction : Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients causing chemotherapy treatment delays, dose reductions, and discontinuation. A major unmet clinical need, there is no FDA-approved agent available to manage CIT. Given this, we developed clinical pathways to treat CIT at 4 large academic hospitals. Data using romiplostim to manage CIT is limited to small single-center studies and case series of solid tumor patients only. We performed the first large multicenter study of romiplostim for CIT, including both solid tumor and non-myeloid hematologic malignancy patients. Methods : We retrospectively collected demographics, cancer and chemotherapy data, romiplostim dosing, weekly platelet counts (Plt), and outcomes of romiplostim support for patients treated on institutional romiplostim CIT pathways from 2009-2019. For solid tumor patients, 2 institutions utilized intracycle dosing (romiplostim administered on average twice monthly on chemotherapy-off weeks) and 2 utilized standard weekly romiplostim dosing, facilitating comparison of dosing strategies. Romiplostim response was defined as a median on-romiplostim Plt of ≥75×109/L and at least 30×109/L higher than baseline. Baseline characteristics were analyzed for predictors of romiplostim non-response using multivariate logistic regression. Wilcoxon signed-rank and Mann-Whitney U tests compared paired and unpaired groups and Chi square and Fisher's exact tests compared categorical outcomes. Results : 173 patients (153 solid tumor, 20 lymphoid malignancy) were treated for CIT with romiplostim to facilitate ongoing chemotherapy administration, with 170 (98%) receiving a median (range) of 4 (1-36) additional chemotherapy cycles over 10 (2-125) weeks of romiplostim support. A total of 61.3 patient-years of romiplostim treatment of CIT were analyzed for effectiveness and safety. Table 1 lists baseline patient characteristics and Table 2 details chemotherapy regimens precipitating CIT and supported on romiplostim. Median per-patient Plt on romiplostim was significantly higher than baseline (all patients, 112×109/L vs. 54×109/L, P&amp;lt;0.001; solid tumor patients, 116×109/L vs. 60×109/L, P&amp;lt;0.001), Figure 1. Median romiplostim starting dose was 3 µg/kg/week, which was also the median optimized romiplostim dose (dose achieving Plt &amp;gt;100×109/L). While on romiplostim, bleeding occurred in 7.5% of patients and venous thromboembolism occurred in 4.6% (at Plt 65-306×109/L). Compared with intracycle romiplostim dosing, weekly romiplostim dosing resulted in higher median Plt (Figure 2) and fewer chemotherapy delays/dose reductions with no difference in bleeding or thrombotic events (Table 3). Characteristics of solid tumor patients predicting non-response to romiplostim per multivariate regression included biopsy-proven bone marrow invasion by tumor (P&amp;lt;0.001), prior pelvic irradiation (P=0.029), and prior temozolomide (P=0.031) (Figure 3), with only 23%, 20%, and 46% of patients, respectively, achieving a romiplostim response compared with 82% of all other solid tumor patients. Plt improvement with romiplostim was modest in patients with myeloma (N=7, median per-patient Plt 39×109/L with romiplostim vs. 19×109/L at baseline, P=0.078) and aggressive lymphoma (N=13, 47×109/L with romiplostim vs. 23×109/L at baseline, P=0.033), Figure 3, with only 35% receiving more than 1 additional chemotherapy cycle on romiplostim. All myeloma and lymphoma patients were dosed weekly and had extensive bone marrow involvement by malignancy. Conclusions : We present results of romiplostim treatment of CIT in a large cohort of 173 cancer patients, including lymphoid malignancies. Dosing strategies were compared and predictors of non-response were evaluated. Romiplostim was highly effective in solid tumor patients with CIT, allowing chemotherapy administration. Bleeding and thrombosis rates were similar to the general cancer patient population. Both weekly and intracycle dosing were effective and equally safe, but weekly dosing maintained higher Plt overall and higher Plt nadirs with fewer chemotherapy dose reductions or treatment delays. Bone marrow invasion, pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Romiplostim had modest effectiveness to manage CIT in lymphoid malignancy patients with underlying bone marrow involvement. Disclosures Al-Samkari: Moderna: Consultancy. Parnes:Sunovion: Consultancy, Other: Safety monitoring board; Hoffman LaRoche: Research Funding; Genentech: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Other: owning stock . Connors:Portola: Other: scientific ad boards; Abbott: Consultancy; Bristol Myer-Squibb: Consultancy, Other: Scientific Ad boards; Eli Lilly: Consultancy. Kuter:Up-to-Date: Consultancy, Honoraria, Patents &amp; Royalties: 3 Up-to-Date chapters; Shinogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kezar: Research Funding. OffLabel Disclosure: Off-label use of the thrombopoietin receptor agonist romiplostim to treat chemotherapy-induced thrombocytopenia is discussed.

2203 Rare Presentation of a Mast Cell Neoplasm as Liver Fibrosis

INTRODUCTION: Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis mainly involving the liver and spleen. Clinical manifestations of the disease include severe anemia, marked hepatosplenomegaly, constitutional symptoms, cachexia, bone pain, pruritus, thrombosis, and bleeding. Super imposed mast cell neoplasm, in a patient with myelofibrosis is rare. Ascites and liver enzyme derangement as the only presenting symptom of these hematological malignancies, is seldom seen. CASE DESCRIPTION/METHODS: 54-year-old female, with what was originally thought to be newly diagnosed, decompensated cirrhosis, who was admitted to the hospital with worsening dyspnea and abdominal pain. The patient was suspected to be septic, and admitted to the MICU. Biochemical work up revealed a total bilirubin of 6.5, AST 65, ALT 32, INR 1.3, WBC 28k and platelet count of 12,000. However, during her hospital stay she continued to have worsening of jaundice and liver enzyme derangement, thus the hepatology service was consulted. The patient’s labs were consistent with alcoholic liver disease, but the patient vehemently denied heavy alcohol use. Given the severe thrombocytopenia, out of proportion to usual levels seen in cirrhosis, the hematology/oncology service was consulted. Trans-jugular liver biopsy showed extramedullary hematopoiesis and myelofibrotic changes with superimposed mast cell neoplasm. Subsequently, bone marrow biopsy also revealed erythroid hyperplasia with marked dyserythropoiesis, consistent with myelodysplastic syndrome, in addition to extensive bone marrow involvement by malignant mast cell neoplasm. DISCUSSION: Resultant hepatosplenomegaly from PMF in patients may lead to non-cirrhotic portal hypertension, which can lead to variceal bleeding or ascites. These symptoms prior to systemic manifestations of a myeloproliferative neoplasm, are rare. Acute liver failure, as the initial presentation of PMF and mast cell neoplasm is not commonly reported in medical literature. The overall prognosis is generally poor with liver involvement an indicator of an advanced stage of the disease.

Leukoerythroblastosis in castration-resistant prostate cancer: A clue to diffuse bone marrow carcinomatosis.

A 66-year-old man with a previous history of advanced prostate cancer failing complete androgen blockade, docetaxel chemotherapy, denosumab, and abiraterone acetate as judged by persistent high serum levels of prostate specific antigen presented with exertional dyspnea, normocytic anemia, and thrombocytopenia. Leukoery - throblastosis was noted in his peripheral blood. Bone marrow examination disclosed diffuse bone marrow carcinomatosis from prostate cancer. Prolonged activated partial thromboplastin time, prothrombin time, and an extremely elevated serum level of Ddimer led to a diagnosis of disseminated intravascular coagulation. Magnetic resonance imaging of spine revealed extensive bone marrow involvement but bone scan showed only scanty bony metastasis. We like to call attention to the importance of prompt bone marrow examination once recognizing leukoerythroblastosis in patients with advanced prostate cancer. Survey of a possible coexistent disseminated intravascular coagulation is as well strongly recommended in this condition.

Microangiopathy in Cancer: Causes, Consequences, and Management.

Thrombotic microangiopathy (TMA) is a syndrome involving fragmentation haemolysis, thrombocytopenia, and thrombosis. A range of disorders including cancer may have TMA as a clinical manifestation. TMA in cancer may be caused by several mechanisms, including systemic microvascular metastases,but may also be due to extensive bone marrow involvement with cancer or secondary necrosis. Chemotherapeutic agents may also cause associated TMA through a range of different mechanisms. Gemcitabine, platinum-based drugs, mitomycin C, and proteasome inhibitors are known to cause TMA in cancer patients. Transplant-associated TMA (TA-TMA) may affect either solid organ or HSCT patients. TA-TMA remains a difficult complication to address due to its high mortality rate, lack of standard diagnostic criteria, and limited therapeutic options. The challenge of cancer-associated TMA is furthered by the fact that plasma exchange is ineffectivein its management.

A Phase I First-in-Human Clinical Trial of CD19-Targeted 19-28z/4-1BBL “Armored” CAR T Cells in Patients with Relapsed or Refractory NHL and CLL Including Richter's Transformation

A Phase I First-in-Human Clinical Trial of CD19-Targeted 19-28z/4-1BBL “Armored” CAR T Cells in Patients with Relapsed or Refractory NHL and CLL Including Richter's Transformation

Ex Vivo Evidence for the Combination of Immune Checkpoint Inhibition with TGF-β Blockade to Enhance Anti-Tumor T Cell Responses in Multiple Myeloma

Immunosuppressive milieu of multiple myeloma is associated with various cellular and non-cellular factors that foster immune escape leading to tumor progression. While immune checkpoint inhibitors have achieved significant clinical success in many types of solid tumors, recent clinical trials of immune checkpoint blockade performed in patients with multiple myeloma failed to demonstrate significant anti-tumor efficacy. To enhance the clinical efficacy of immune checkpoint blockade in multiple myeloma, elaborate characterization of tumor antigen-specific T cells is an essential prerequisite. In the present study, we investigated the immunophenotypic and functional characteristics of tumor antigen-specific T cells in patients with multiple myeloma. In addition, using direct ex vivo experimental techniques, we tried to examine how to manipulate the immunosuppressive microenvironment to maximize anti-myeloma responses of the tumor-specific T cells.We first tried to define and characterize CD8+ T cell population capable of specifically recognizing and reacting to myeloma cells in bone marrow of myeloma patients using MHC multimer technique. In selected patients, we could successfully define CD8+ T cell population specifically recognizing the HLA-A*0201-restricted epitopes (either “SLLMWITQC” or “LLLGIGILV”), included in myeloma tumor antigens NY-ESO-1 and HM1.24. The vast majority of myeloma-antigen specific CD8+ T cells expressed high level of PD-1 and also co-expressed other types T cell inhibitory receptors. More strikingly, PD-1+ myeloma-specific CD8+ T cells had a distinct pattern of transcriptional factor expression, high level of Eomes and low level of T-bet (EomeshiT-betlo), indicating that they were profoundly exhausted functionally and that a simple blockade of PD-1/PD-L1 binding might not be enough to reinvigorate their anti-myeloma activity.Consistent with the immunophenotypes of myeloma-specific CD8+ T cells, malignant plasma cells in bone marrow of myeloma patients, defined as CD14-CD19-CD138+CS1+CD56hi, also expressed PD-L1 abundantly, compared to normal plasma cells, suggesting that PD-1/PD-L1 axis plays a major role in making myeloma-recognizing T cells unresponsive to TCR stimulation. Interestingly, in addition to tumor cells, various types of immune cells comprising myeloma microenvironment also highly express PD-L1. Indeed, in response to ex vivo TCR stimulation with anti-CD3, CD8+ T cells from myeloma bone marrow showed lower proliferation and reduced production of anti-tumor effector cytokines (INF-γ and TNF-α), compared to marrow-infiltrating CD8+ T cells of diffuse large B cell lymphoma and Hodgkin lymphoma patients with extensive bone marrow involvement. However, even in the presence of anti-PD-1, myeloma-specific responses of marrow-infiltrating CD8+ T cells was only modestly improved in terms of proliferation and cytokine production.Next, we investigated whether blocking TGF-β signaling in combination with PD-1/PD-L1 axis blockade could restore the function of marrow-infiltrating CD8+ T cells of myeloma patients, since TGF-β produced by clonal plasma cells and bone marrow stromal cells is critical in immunosuppressive microenvironment of multiple myeloma. To this end, we found that combination of TGF-β signaling blockade (either anti-TGF-β1 or Galunisertib, a small molecule inhibitor of TGF-β receptor I) with anti-PD-1 significantly increased the frequencies of IFN-γ- and/or TNF-α-producing CD8+ T cells in response to ex vivo TCR stimulation, compared to a single PD-1 or a single TGF-β blockade. Likewise, myeloma antigen-specific proliferation of CD8+ T cells was significantly enhanced with addition of TGF-β signaling blockade.Taken together, although PD-1/PD-L1 axis acts as a major component of immunosuppressive milieu in multiple myeloma, the efficacy of PD-1 blockades in multiple myeloma might be hampered by complicated microenvironment consisting of T cell-intrinsic and -extrinsic factors. Our results provide an ex vivo evidence of incorporating TGF- β signaling blockade to immune checkpoint inhibition to enhance anti-tumor T cell responses in multiple myeloma DisclosuresNo relevant conflicts of interest to declare.

An Unusual Cause of Obscure Gastrointestinal Bleeding Unmasked by Video Capsule Endoscopy

Follicular lymphoma (FL) is the most common type of non-Hodgkin's lymphoma in the West, usually detected in lymph nodes. Gastrointestinal tract (GIT) is a common site of extra-nodal disease. We report a case of atypical GI-FL diagnosed as a consequence of investigations for microcytic anemia. A 73-year-old gentleman was referred for evaluation of iron-deficiency anemia, presumed GI source. Physical examination was grossly normal. Initial age-appropriate colonoscopy revealed a cecal hyperplastic polyp and non-bleeding internal hemorrhoids. Six weeks later, upper endoscopy for new-onset melena revealed grade C esophagitis, erosive gastritis, and single small angioectasia in anterior duodenal bulb, unlikely to account for the severity of blood loss. Duodenal biopsy was negative for celiac disease. Video capsule endoscopy (VCE) was performed for worsening anemia necessitating blood transfusion. Active oozing spot amongst an area of erythema, erosions, small ulcers and likely luminal narrowing and stricture was evident in the distal jejunum/proximal ileum. The capsule did not reach the cecum. Due to retained capsule and luminal stricture, CT enterography was performed. This revealed large anterior mediastinal, retroperitoneal, pelvic masses and extensive severe small bowel wall thickening, compatible with possible nodal and extra-nodal metastatic lymphoma. The capsule has since passed. Subsequent pelvic mass biopsy showed low-grade FL. Further staging including PET confirmed atypical involvement with most intense uptake in the mesentery, omentum and pleura, and extensive nodal and bone marrow involvement. GI-FL is a rare entity, generally affecting the small intestines. It is not always possible to determine the primary site of origin of GI-FL. It could either arise from extra-intestinal regions and present in the GIT at an advanced stage, or arise primarily in the GIT and disseminate to involve lymph nodes or other extra-intestinal sites. Optimal work-up and treatment plan is not well established. Endoscopic evaluation of the entire GIT and whole body PET are required for accurate staging. Based on the stage, treatment options include watch and wait approach, surgery, chemotherapy, radiotherapy, immune-radiotherapy or a multi-modal approach. Chemotherapy with rCHOP was initiated on our patient. Initially he responded to the regimen. Unfortunately, the disease turned aggressive shortly afterwards, and he subsequently transitioned to palliative care.1935_A Figure 1. Capsule endoscopy demonstrating edema, erosion, luminal narrowing and oozing in distal jejunum/proximal ileum.1935_B Figure 2. Active oozing from the erythematous, inflamed area with luminal narrowing narrowing in the distal jejunum/proximal ileum noted on capsule endoscopy.1935_C Figure 3. Capsule endoscopy demonstrating edematous, inflamed area in distal jejunum

Primary lymphoma of bone, myeloma mimicker: a case report and review of literature

Primary lymphoma of the bone (PLB) primarily arising from the medullary cavity is an extremely rare entity, with only limited number of studies and sporadic cases reported in the literature. The current study presents one case of PLB presented with unique presentation and treated with chemotherapy only. A 66 year old male presented with severe pain in the left hip that persisted for two months. Initial laboratory work up showed anemia, hypercalcemia and increase in free light chains kappa to lambda ratio, a diagnosis of multiple myeloma was suspected, magnetic reso¬nance imaging of the vertebral spine extensive involvement of bone marrow of the vertebrae. An 18F fluorodeoxyglucose positron emission tomography computed tomography (FDG PET CT) scan showed widely scattered moderate to intense uptake in multiple lytic of skeleton, Impression was : Image compatible with extensive multiple myeloma, No extra osseous involvement was found. Bone marrow examination was performed confirmed a diagnosis of extensive bone marrow involvement by High grade B-cell neoplasm with areas of bone marrow necrosis. The patient received six cycles of R-CHOP regimen (Rituximab, cyclo-phosphamide, Anthracycline, vincristine and prednisone) and achieved a complete response, as confirmed by FDG PET CT. At present, the patient is in a good condi¬tion.so this patient presentation mimicking multiple myeloma, which represent diagnostic dilemma. Primary lymphoma of the bone is rare disease entity, there is no strong evidence supporting some diagnostic and therapeutic decisions, and therefore, case presentation of the rare disease may facilitate treatment of similar diseases. A review of the literature to elucidate the clinical, radiological, pathological phenotype and optimal treatment of PLB done.