Programmed death-ligand 1 expression in patients with primary or secondary myelofibrosis.

BACKGROUND: It has been described in mice models that myeloproliferative neoplasm (MPN) with JAK2-V617F mutation has an increased expression of programmed death-ligand 1 (PD-L1) in megakaryocytes leading to cancer immune evasion by inhibiting the T-lymphocytes. AIMS: To quantify and compare the PD-L1 expression on bone marrow (BM) of patients with MPN JAK2 positive, negative, and normal controls. METHODS: We collected BM of patients with MPN JAK2 positive, negative and normal controls from 1990 to 2019. We also created a scoring system to quantify PD-L1 expression in megakaryocytes. RESULTS: We obtained 14 BM with JAK2 positive PMF, 5 JAK2 negative PMF, and 10 patients with normal BM biopsies. PD-L1 expression was higher in the JAK2 positive group compared with the control group with a score of 212.6 versus 121.1 (t-value 2.05, p-value 0.025). In addition, the score was higher in the PMF group regardless of JAK2 mutational status when compared with the control group with score of 205.9 versus 121.1 (t-value 2.12, p-value 0.021). There was no difference in the PD-L1 score between the JAK2 negative versus the control group 187.2 versus 121.1 (t-value 1.02, p-value 0.162). CONCLUSION: These findings suggest that PMF patients with a JAK2 mutation have a higher PD-L1 expression in megakaryocytes compared with the control group. We postulate that the combination of checkpoint and JAK2 inhibitors may be an active treatment option in JAK2 mutated PMF given the higher PD-L1 expression.

Testicular involvement in mantle cell lymphoma: An analysis of 16 patients.

Mantle cell lymphoma (MCL) with testicular involvement is a rare presentation and only a few cases have been described in the literature. We present a case of MCL with testicular involvement and the first analysis of all previously reported cases assessing trends in immunohistochemical features, prognostic indicators, and survival. Our data suggest that among all MCL, testicular MCL is more likely to present with aggressive features: blastoid/pleomorphic morphology, high Ki-67 proliferative index, and CNS involvement. Testicular MCL is also associated with shorter overall survival.

Profiling the activity of the para-caspase MALT1 in B-cell acute lymphoblastic leukemia for potential targeted therapeutic application.

B cell acute lymphoblastic leukemia (B-ALL) remains a hard-to-treat disease with a poor prognosis in adults. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. Inhibition of MALT1 in preclinical models has proven efficacious in many B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of its inhibition. Targeting MALT1 with both Z-VRPR-fmk and MI-2 efficiently kills B-ALL cells independent of the cell-of-origin (pro, pre, mature) or the presence of the Philadelphia chromosome, and spares normal B-cells. The mechanism of cell death was through apoptotic induction, mostly in cycling cells. The proteolytic activity of MALT1 can be studied by measuring its ability to cleave its substrates. Surprisingly, with the exception of mature B-ALL, we did not detect cleavage of MALT1 substrates at baseline, nor after proteasomal inhibition or following activation of pre-BCR. To explore the possibility of a distinct role for MALT1 in B-ALL, independent of signaling through BCR, we studied the changes in gene expression profiling following a 24-hour treatment with MI-2 in 12 B-ALL cell lines. Our transcriptome analysis revealed a strong inhibitory effect on MYC-regulated gene signatures, further confirmed by Myc protein downregulation, concomitant with an increase in the Myc degrader FBXW7. In conclusion, our evidence suggests a novel role for MALT1 in B-ALL through Myc regulation and provides support for clinical testing of MALT1 inhibitors in B-ALL.

Establishment and characterization of a new mantle cell lymphoma cell line with a NOTCH2 mutation, Arbo.

Cell lines represent an essential tool used in preclinical research. Most hematologic malignancies have a wide array of cell lines representing their respective molecular and pathologic spectra. In mantle cell lymphoma (MCL), cell lines become specifically valuable in view of the heterogeneity of this disease. Unfortunately, the number of MCL cell lines that are available for the research community remains small, with only nine cell lines available for purchase through the American Type Culture Collection (ATCC). We have established a novel blastoid MCL cell line, isolated from the malignant pleural effusion of a 69-year-old male with refractory MCL. Arbo was fully characterized with cytogenetics, immunophenotyping, whole exome sequencing and drug sensitivity assays. One of the most notable mutations identified in Arbo (but not in normal tissue) was the missense mutation NOTCH2 R2400*, which has been proposed as a clinically significant mutation in MCL seen in 5% of cases. NOTCH2 R2400* results in a truncated Notch2 protein, leading to a more stable and active protein. Using pharmacologic inhibition of Notch2, we showed a dependence of Arbo on NOTCH2 signaling, as well as a link between CD23 expression on Arbo and NOTCH2 activity. Arbo represents a NOTCH2 mutated model that is useful in MCL as well as other lymphomas with such mutation. We plan to deposit Arbo at the ATCC to be available for the research community.

Co-management strategies for acute myeloid leukemia patients in the community setting.

The treatment landscape for acute myeloid leukemia (AML) has changed substantially in recent years. The introduction of newer therapies, including oral agents, less myelosuppressive agents, and parenteral regimens suitable for outpatient administration, has made it feasible for select patients to receive therapy in the outpatient setting and in community practices. Thorough patient evaluation (including molecular testing), planned supportive care (eg, transfusion support, antimicrobial prophylaxis), and vigilant patient monitoring (for tumor lysis syndrome and adverse events) by a multidisciplinary team are required for successful management of patients both in the community and at specialized leukemia centers. Some patients are unable or unwilling to travel to larger academic centers for treatment, and treatment of AML in the community setting may have potential advantages compared to less conveniently located academic/leukemia centers. This includes reduction of financial hardship for patients and their families and often better opportunities for family/caregiver support. Additionally, partnership between community practices and academic/leukemia centers is often crucial to optimizing AML management for many patients, as collaboration may facilitate access to additional expertise and trials, multidisciplinary teams for supportive care, easier transition to hematopoietic cell transplantation, and access to sophisticated molecular testing. In this review, we discuss AML treatment and management in the community setting, available therapies, and circumstances in which a referral to and co-management with an academic/leukemia center is more strongly recommended.

CD5-negative mantle cell lymphoma: clinicopathologic features of an indolent variant that confers a survival advantage.

Conventionally, mantle cell lymphoma (MCL) is an aggressive CD5-positive B-cell malignancy with poor prognosis and limited survival. However, a small subset of patients presents with indolent disease and can be managed on a 'watch and wait' approach. CD5-negative MCL has recently been recognized as a more favorable variant of MCL, but its clinical and biological implications remain ill-defined. We performed the most extensive review to-date of all reported cases of CD5-negative MCL and included unpublished cases diagnosed at our institutions to further characterize this disease subset. Based on our analysis of 356 cases of CD5-negative MCL, we conclude that median overall survival exceeds 14 years and is independent of favorable prognostic markers such as leukemic non-nodal disease, absence of SOX11, and low Ki-67.

Systemic vs. intrathecal central nervous system prophylaxis in primary adrenal/renal diffuse large b-cell LYMPHOMA: A multi-institution retrospective analysis and systematic review.

Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma subtype. Primary adrenal and renal lymphomas (PARL) exhibit a high predilection for the central nervous system (CNS). Therefore, current guidelines support the use of CNS prophylaxis in PARL, particularly in cases of high-risk Central Nervous System International Prognostic Index (CNS-IPI). However, the route of administration (i.e. systemic vs. intrathecal chemotherapy) has not been clearly elucidated. With this in mind, we initiated an international collaboration and literature review to analyze 50 patient cases, 20 of which received CNS prophylaxis. Based on our analysis, we conclude that PARL may indicate a need for CNS chemo-prophylaxis in the form of systemic high-dose methotrexate (HD-MTX) over intrathecal methotrexate (IT-MTX), although IT-MTX may still have utility in certain cases.

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial.

BACKGROUND: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial. METHODS: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1-80) oral azacitidine treatment cycles or 6 (1-73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3-4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. CONCLUSION: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Cancer and COVID-19: analysis of patient outcomes.

Background: We sought to investigate the outcomes associated with COVID-19 disease in cancer patients. Methods: We conducted a retrospective cohort study of laboratory-confirmed COVID-19 patients. Results: Of the 206 patients included, 57 had at least one preexisting malignancy. Cancer patients were older than noncancer patients. Of the 185 discharged cases, cancer patients had a significantly higher frequency of unplanned reintubation (7.1% vs 0.9%, p < 0.049), and required longer hospital stay (8.58 ± 6.50 days versus 12.83 ± 11.44 days, p < 0.002). Regression analysis revealed that obesity and active smoking were associated with an increased risk of mortality. Conclusion: Outcomes in COVID-19 appear to be driven by obesity as well as active smoking, with no difference in mortality between cancer and noncancer patients.

In this study, we aimed to investigate how COVID-19 affected cancer patients and whether this altered their survival outcomes. To do this, we examined data from a database of patients who have passed through our institution ­ a retrospective cohort analysis. Of the 206 patients we included in the study from this database, 57 had at least one preexisting cancer. Cancer patients tended to be older than noncancer patients. Of the 185 discharged patients, cancer patients required longer hospital stays, but there was no difference in mortality. Disease complications and intensive care unit admission with obesity and active smoking put patients in our cohort at increased risk of death. To conclude, outcomes in COVID-19 patients appear to be driven by obesity as well as active smoking, with no difference in mortality between cancer and noncancer patients.

Successful treatment of "accelerated" chronic lymphocytic leukemia with single agent ibrutinib: A report of two cases.

"Accelerated" chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.

The utility of hyperbaric oxygen therapy in post-transplant cyclophosphamide-induced hemorrhagic cystitis: a case report and review of the literature.

BACKGROUND: To date, there are only a few case reports of cyclophosphamide (Cy)-induced hemorrhagic cystitis (HC) in adult or pediatric allogeneic stem cell transplant (SCT) patients treated successfully with hyperbaric oxygen (HBO). In all the reported cases, Cy was used as a part of the conditioning regimen, rather than post-transplant for graft-versus-host-disease (GVHD) prophylaxis. More recently, the risk of HC in allogeneic SCT is further increased by the widespread use of post-transplantation cyclophosphamide (PTCy) as a highly effective strategy for GVHD prophylaxis. This is the first case reported of PTCy-induced HC successfully treated with HBO to the best of our knowledge. CASE PRESENTATION: In this article, we present a 58-year-old Caucasian male case of allogeneic SCT complicated by severe HC following PTCy, which was successfully treated with HBO, eliminating the need for cystectomy. CONCLUSION: HBO can be a safe, noninvasive, alternative treatment modality for PTCy-induced HC developing in allogeneic SCT patients.

The prognostic implications of tetraploidy/near-Tetraploidy in acute myeloid leukemia: a case series and systematic review of the literature.

The prognostic significance and optimal management of tetraploidy/near-tetraploidy acute myeloid leukemia (T/NT AML) remains unclear given its limited data. This is especially true after factoring in additional chromosomal alterations, which carry their own prognostic weight. Here, we analyze 128 cases of T/NT in AML from the literature along with two additional cases, which is the largest review of this subject to date. Based on our retrospective analysis, we found that regardless of the risk status attributed to cytogenetics, the prognosis of tetraploid or near-tetraploid AML is dismal and should be incorporated within the unfavorable risk group. Complete remission is paramount to survival in this population. Specific induction protocols for high-risk AML appear to have higher rates of complete remission in the T/NT AML population. Moreover, longer overall survival can be achieved with chemotherapy followed by allogeneic stem cell transplantation at first complete remission.

Free light chains injure proximal tubule cells through the STAT1/HMGB1/TLR axis.

Free light chains (FLCs) induce inflammatory pathways in proximal tubule cells (PTCs). The role of TLRs in these responses is unknown. Here we present findings on the role of TLRs in FLC-induced PTC injury. We exposed human kidney PTC cultures to κ and λ FLCs and used cell supernatants and pellets for ELISA and gene expression studies. We also analyzed tissues from Stat1-/- and littermate control mice treated with daily i.p. injections of a κ FLC for 10 days. FLCs increased the expression of TLR2, TLR4, and TLR6 via HMGB1, a damage-associated molecular pattern. Countering TLR2, TLR4, and TLR6 through GIT-27 or specific TLR siRNAs reduced downstream cytokine responses. Blocking HMGB1 through siRNA or pharmacologic inhibition, or via STAT1 inhibition, reduced FLC-induced TLR2, TLR4, and TLR6 expression. Blocking endocytosis of FLCs through silencing of megalin/cubilin, with bafilomycin A1 or hypertonic sucrose, attenuated FLC-induced cytokine responses in PTCs. IHC showed decreased TLR4 and TLR6 expression in kidney sections from Stat1-/- mice compared with their littermate controls. PTCs exposed to FLCs released HMGB1, which induced expression of TLR2, TLR4, and TLR6 and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knockdown, HMGB1 inhibition, and TLR knockdown each rescued PTCs from FLC-induced injury.

Primary Dural Diffuse Large B-cell Lymphoma: A Comprehensive Review of Survival and Treatment Outcomes.

Primary dural diffuse large B-cell lymphoma (PD-DLBCL) is a rare and aggressive B-cell non-Hodgkin lymphoma that can present in intracranial or intraspinal locations. Although the optimal management is unknown, PD-DLBCL therapy is often mirrored after primary central nervous system lymphoma therapy and aggressive treatment with a high dose methotrexate-based regimen is frequently used. Our comprehensive, retrospective study of 24 reported cases of PD-DLBCL provide the most complete analysis of this rare disease including data on biology, treatment outcomes, and survival. Our findings demonstrate good outcomes following induction treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), suggesting that these cases can be treated as DLBCL rather than primary central nervous system lymphoma, obviating the need for more aggressive and toxic approaches. The durable responses following R-CHOP also confirm that PD-DLBCL is not protected by the blood brain barrier.

RUNX1 deletion/amplification in therapy-related acute myeloid leukemia: A case report and review of the literature.

Intrachromosomal amplification of chromosome 21 (iAMP21) is a rare occurrence in acute myeloid leukemia (AML). We describe here a case of AML with apparent amplification of RUNX1 by cytogenetics and FISH. A 39-year-old female in remission from stage IIIa breast cancer was diagnosed with therapy-related AML (t-AML). The patient's bone marrow was hypocellular for her age (30-40%) with 25% blasts. Cytogenetic analyses revealed a complex karyotype, characterized by rearrangements in chromosomes 1, 5, 17, 20, an additional unidentified marker chromosome, and apparent amplification of chromosome 21. Fluorescence in situ hybridization detected deletions of CKS1B, EGR1, TP53, and apparent amplification of RUNX1 (6-8 signals). Array comparative genomic hybridization (array-CGH) detected amplification of the 5' non-coding region of RUNX1 and deletion of the 3' coding region of RUNX1. These results show that this is not a true case of iAMP21 and suggest that RUNX1 is not the primary target of amplification.