Myeloproliferative neoplasms (MPN) are chronic stem cell disorders characterized by enhanced proliferation of myeloid cells, immune deregulation, and drug resistance. JAK2 somatic mutations drive the ...disease in 50–60% and CALR mutations in 25–30% of cases. Published data suggest that JAK2‐V617F‐mutated MPN cells express the resistance‐related checkpoint PD‐L1. By applying RNA‐sequencing on granulocytes of 113 MPN patients, we demonstrate that PD‐L1 expression is highest among polycythemia vera patients and that PD‐L1 expression correlates with JAK2‐V617F mutational burden (R = 0.52; p < .0001). Single nucleotide polymorphism (SNP) arrays showed that chromosome 9p uniparental disomy (UPD) covers both PD‐L1 and JAK2 in all MPN patients examined. MPN cells in JAK2‐V617F‐positive patients expressed higher levels of PD‐L1 if 9p UPD was present compared to when it was absent (p < .0001). Moreover, haplotype‐based association analyses provided evidence for germline genetic factors at PD‐L1 locus contributing to MPN susceptibility independently of the previously described GGCC risk haplotype. We also found that PD‐L1 is highly expressed on putative CD34+CD38− disease‐initiating neoplastic stem cells (NSC) in both JAK2 and CALR‐mutated MPN. PD‐L1 overexpression decreased upon exposure to JAK2 blockers and BRD4‐targeting agents, suggesting a role for JAK2‐STAT5‐signaling and BRD4 in PD‐L1 expression. Whether targeting of PD‐L1 can overcome NSC resistance in MPN remains to be elucidated in forthcoming studies.
Randomized comparison between KTd and KRd induction followed by second randomization to carfilzomib in transplant‐ineligable patients with newly diagnosed multiple myeloma.
Myeloproliferative neoplasms (MPN) are characterized by uncontrolled expansion of myeloid cells, disease‐related mutations in certain driver‐genes including JAK2, CALR, and MPL, and a substantial ...risk to progress to secondary acute myeloid leukemia (sAML). Although behaving as stem cell neoplasms, little is known about disease‐initiating stem cells in MPN. We established the phenotype of putative CD34+/CD38− stem cells and CD34+/CD38+ progenitor cells in MPN. A total of 111 patients with MPN suffering from polycythemia vera, essential thrombocythemia, or primary myelofibrosis (PMF) were examined. In almost all patients tested, CD34+/CD38− stem cells expressed CD33, CD44, CD47, CD52, CD97, CD99, CD105, CD117, CD123, CD133, CD184, CD243, and CD274 (PD‐L1). In patients with PMF, MPN stem cells often expressed CD25 and sometimes also CD26 in an aberrant manner. MPN stem cells did not exhibit substantial amounts of CD90, CD273 (PD‐L2), CD279 (PD‐1), CD366 (TIM‐3), CD371 (CLL‐1), or IL‐1RAP. The phenotype of CD34+/CD38− stem cells did not change profoundly during progression to sAML. The disease‐initiating capacity of putative MPN stem cells was confirmed in NSGS mice. Whereas CD34+/CD38− MPN cells engrafted in NSGS mice, no substantial engraftment was produced by CD34+/CD38+ or CD34− cells. The JAK2‐targeting drug fedratinib and the BRD4 degrader dBET6 induced apoptosis and suppressed proliferation in MPN stem cells. Together, MPN stem cells display a unique phenotype, including cytokine receptors, immune checkpoint molecules, and other clinically relevant target antigens. Phenotypic characterization of neoplastic stem cells in MPN and sAML should facilitate their enrichment and the development of stem cell‐eradicating (curative) therapies.
The 2016 revised WHO criteria for the diagnosis of pre‐fibrotic/early primary myelofibrosis (pre‐PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, ...leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre‐PMF patients and compared them to 225 ET cases. More than 91% of pre‐PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre‐PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre‐PMF and ET. Molecular characterization showed differences in survival in pre‐PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre‐PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre‐PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of ...MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1−/− mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.
•JAK1/2 inhibitor treatment in myelofibrosis is associated with an increased risk for aggressive B-cell lymphomas.•Patients at risk have a preexisting B-cell clone in their bone marrow, which can be identified by polymerase chain reaction.
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Abstract Immune-mediated hematological diseases are rare, but typical paraneoplastic syndromes. We have critically analyzed 68 published cases of an association of autoimmune thrombocytopenia (ITP) ...and solid cancers. Such cases occurred in a variety of cancers. They were most common in patients with lung and breast cancer, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers. ITP occurred in about half of the patients concurrently with cancer, in about 25% prior to cancer and in others some time after diagnosis and treatment of cancer. In the latter patients ITP was either a sign of recurrence of cancer or had other causes. In most patients ITP responded to steroid treatment. There were only few patients who had a complete response of ITP after surgical removal or chemotherapy of the cancer and there was only one patient (ITP prior to cancer) in whom a long lasting complete remission of ITP after cancer resection could be ascribed solely to cancer resection. We believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. In patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the treatment of choice.
The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of ...action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.
Summary
In patients with myelodysplastic syndromes (MDS), sole 20q deletion del(20q) is a recurrent favourable abnormality. We studied additional molecular and cytogenetic lesions and their ...prognostic impact in 305 MDS patients with del(20q) (229 males/76 females; 29–90 years). All patients were investigated by cytomorphology and chromosome banding analysis (CBA), subsets by fluorescence in situ hybridization, molecular mutation screening, and array comparative genomic hybridization (aCGH). By aCGH (n = 30), the minimal common deleted region (CDR) was flanked by PTPRT (20q13·11) and EYA2 (20q13·12). 210 (68·9%) patients had ‘early MDS’ without blast increase, 95 (31·1%) ‘advanced’ MDS with blast increase (5–19%). Additional chromosomal abnormalities (ACAs) were detected in 88/305 (28·9%) patients. Patients with advanced MDS more frequently had ACAs (P = 0·003) and had a higher mean number of ACAs (P = 0·020) and of molecular mutations (P = 0·060). Spliceosome mutations were frequent (U2AF1: n = 31/155; 20·0%; SRSF2: n = 31/159; 19·5%; SF3B1mut: n = 8/159; 5·0%). ASXL1mut (25/153; 16·3%) were associated with advanced MDS (P = 0·001). Presence of ≥3 ACAs (P = 0·003) and ASXL1mut (P = 0·002) were associated with worse 2‐year survival. In conclusion, the cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1mut is overrepresented in MDS with del(20q), and ASXL1mut is prognostically adverse.
Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do ...not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response.
The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders.
Among 28 patients with CN,
= 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years,
= 0.039), showed higher overall survival (153months; 58months,
= 0.044) and achieved hematologic response (≥PR) to first-line therapy (
= 0.029), and complete hematologic response (CR) at any time (
= 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days,
= 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (
= <0.001).
In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.
Background
The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small ...phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.
Purpose
To analyze the efficacy and safety of elo/pom/dex in a “real world” cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna.
Findings
We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia.
Conclusion
Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.
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