^
5d
Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.
Clinical • Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation
|
ibrutinib
6d
First, the monotypic B cells are positive for CD5, not typically observed in LPLs; second, there is concurrent AL-type amyloidosis; third, besides commonly encountered MYD88 mutation, the case also harbors CXCR4 mutation. The presence of coexisting amyloidosis, and CXCR4 and TP53 mutations, will undoubtedly affect this patient's prognosis as shown by previous studies.
TP53 (Tumor protein P53) • CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD5 (CD5 Molecule) • SDC1 (Syndecan 1) • MME (Membrane metallo-endopeptidase)
|
TP53 mutation • CD20 positive • MYD88 L265P • CXCR4 mutation • MYD88 mutation • CD5 positive • TP53 R273C
6d
The overall features favored a diagnosis of IgM PCM with a concurrent CD5−/CD10− lymphoproliferative disorder (non-LPL). There can be signifi-cant pathologic overlap between IgM PCM and lymphoplasmacytic lymphoma, with rare cases of composite conditions making it even more complicated; and henceforth careful bone marrow assessment is required, coupled with molecular and cytogenetic analysis.
KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • PAX5 (Paired Box 5) • CD5 (CD5 Molecule) • NCAM1 (Neural cell adhesion molecule 1) • SDC1 (Syndecan 1) • MME (Membrane metallo-endopeptidase)
|
CD20 positive • Chr t(11;14) • MYD88 mutation • CD38 positive • SDC1 positive
9d
The identification of these mutations is very important, because they can modulate the response to new treatments with Bruton's tyrosine kinase (BTK) inhibitors. Thus, the conventional prognostic factors that predict the outcome of these patients (anemia, thrombopenia, high M component, high B2M, and advanced age), must be complemented with the genetic evaluation of the patient, that can help us in the prediction of the risk of transformation from asymptomatic to symptomatic forms (Del6q) and/or from indolent forms of the disease to aggressive lymphomas (CD79b mutations).
Review • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD79B (CD79b Molecule) • B2M (Beta-2-microglobulin)
|
MYD88 L265P • MYD88 mutation • CD79B mutation • CD79B mutation
11d
BGB-3111 provides better safety than another BTK inhibitor, ibrutinib as ibrutinib inhibits the inducible T-cell kinase (ITK) as an off-target effect but BGB-3111 does not inhibit ITK. Taken together, our findings validate that BGB-3111 is a novel and effective BTK inhibitor for MCL-expressing BTK. Hence, it can be harnessed as a potential therapeutic strategy through a combinatorial treatment comprising low-dose BGB-3111 and low-dose BTZ to gain strong anti-cancer effects and better safety for MCL patients.
Journal • PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CASP9 (Caspase 9) • RELA (RELA Proto-Oncogene)
|
BCL2 expression • BTK overexpression
|
ibrutinib • bortezomib • Brukinsa (zanubrutinib)
13d
Furthermore, treatment options have also been developed, and Bruton's tyrosine kinase (BTK) inhibitor has been recently approved for untreated and relapsed/refractory WM/LPL in August 2020 in Japan. In this article, after a brief review of the clinical and biological characteristics of WM/LPL, we discuss the ideal therapeutic algorithm, including novel BTK inhibitor.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
18d
CD34 (CD34 molecule)
|
Mozobil (plerixafor)
18d
In that context, a recent randomised trial of ibrutinib versus zanubrutinib demonstrated arguably more important differences in secondary endpoint toxicity profiles than in the primary response rate. In partnership with our patient community, it is time to develop and iteratively refine a new methodology in our studies: the determination of composite utility endpoints to capture how best patients with indolent lymphoma can both live long and live well. This will take time, a commodity our patients have.
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
ibrutinib • Brukinsa (zanubrutinib)
18d
The INNOVATE study randomized 150 patients with WM to either the combination of ibrutinib plus rituximab or placebo plus rituximab.2 The combination of ibrutinib plus rituximab was associated with a higher major response rate (72% versus 32%) and a higher 30-month PFS rate (82% versus 28%) than the combination of placebo plus rituximab, prompting the approval of the combination of ibrutinib plus rituximab for WM by the FDA in 2018...Three novel covalent BTK inhibitors are under active investigation for WM: zanubrutinib, acalabrutinib and tirabrutinib...The non-covalent BTK inhibitor pirtobrutinib was evaluated in a multicenter phase Iistudy in 26 patients with WM of whom 18 (12 had progressed and 6 were intolerant) were previously exposed to a covalent BTK inhibitor.6 The ORR to pirtobrutinib was 69%...A study evaluating the combination of ibrutinib and venetoclax in treatment-naïve patients with WM is ongoing...The CXCR4 inhibitor mavorixafor is being evaluated in combination with ibrutinib in WM patients who carry CXCR4 mutations. The PI3K inhibitor idelalisib show early efficacy in patients with WM but it seems to be associated with a high rate of liver toxicity.8 A multicenter study evaluating umbralisib in patients with WM has stopped accrual. The anti-CD38 monoclonal antibody daratumumab had a lower-than-expected efficacy rate in WM.9 Dasatanib is an HCK inhibitor being studied in patients with WM progressing on covalent BTK inhibitors. The phospholipid-drug conjugate CLR-131 was recently granted a Fast- Track Designation for WM patients having received two or more prior treatment regimens. In all, the treatment of patients with WM continues evolving. There are many reasons to be optimistic about the future of the treatment landscape of patients with WM.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation • BTK mutation
|
Venclexta (venetoclax) • Rituxan (rituximab) • ibrutinib • Zydelig (idelalisib) • Calquence (acalabrutinib) • Brukinsa (zanubrutinib) • Darzalex IV (daratumumab) • Ukoniq (umbralisib) • pirtobrutinib (LOXO-305) • iopofosine I-131 (I-131-CLR1404) • mavorixafor (X4P-001) • Velexbru (tirabrutinib)
18d
Data from a retrospective review of 63 patients, with known CXCR4 mutational status in 49 patients, treated with bortezomib and rituximab showed no significant difference in PFS or OS when comparing patients with or without CXCR4 mutations.6 A prospective study of 69 patients treated with bendamustine plus rituximab showed no difference in disease response or survival outcomes based on the CXCR4 mutational status.7 Similar results were also reported in a pooled analysis of patients treated with bortezomib, carfilzomib, or ixazomib in the frontline setting.8 No difference in response rates, PFS or OS after frontline treatment initiation was noted between patients with and without CXCR4 mutations...Patients with MYD88WT and CXCR4WT disease, which constitute 5–10% of patients with WM, have specific clinical characteristics, such as shorter overall survival (OS) and increased risk of transformation to aggressive lymphoma.10–12 Bendamustine plus rituximab should be considered an option given reported efficacy in a retrospective study.13 However, a prospective study suggested a shorter PFS in the six MYD88WT patients.2 Lower response rates to single agent ibrutinib were reported in a study using an allele-specific polymerase chain reaction (AS-PCR) assay in CD19-selected bone marrow cells to assess MYD88 mutational status.14 In the INNOVATE study, the combination of ibrutinib plus rituximab was associated with an ORR of 81%, a major response rate of 63%, a VGPR rate or 27% and a 30-month PFS rate of 80% in patients with MYD88WT and CXCR4WT disease.9 In this study, however, the MYD88 mutational status was assessed in 136 patients using next-generation sequencing (NGS) in unselected bone marrow cells...In the acalabrutinib study, 50 of 106 (47%) of the participants were genotyped and 14 (28%) had MYD88WT disease...Zanubrutinib therapy was associated with an ORR, major response rate and VGPR rate of 80%, 50% and 27%, with an 18-month PFS rate of 68%. Genomic profiling has emerged as a potential approach to tailoring treatment options in patients with WM.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD19 (CD19 Molecule)
|
CXCR4 mutation • MYD88 mutation • MYD88 mutation + CXCR4 mutation
|
Rituxan (rituximab) • ibrutinib • bortezomib • Ninlaro (ixazomib) • Calquence (acalabrutinib) • Brukinsa (zanubrutinib) • carfilzomib • bendamustine
22d
These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (P<0.05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.
Clinical • Journal
|
TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • KMT2D (Lysine Methyltransferase 2D) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • SPI1 (Spi-1 Proto-Oncogene)
|
TP53 mutation • Chr del(17p) • KMT2D mutation • CXCR4 mutation • MYD88 mutation
23d
P2, N=72, Recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Jul 2021 --> Jul 2022
Clinical • Trial completion date • Trial primary completion date
|
FLT3 (Fms-related tyrosine kinase 3)
|
Chr del(5q)
|
fludarabine IV • thiotepa • cyclophosphamide intravenous • mycophenolate mofetil • mycophenolate sodium • tacrolimus XR • tacrolimus intravenous
26d
This MYD88 mutation is associated with several B neo- plasms. It is detectable in more than 90% of patients with Waldenström macroglobulinemia and lymphoplasmacytic lymphoma. The immunohistochemical and molecular characterization of the lym- phoid tissue associated with primary amyloidosis allows a more complete typing of the underlying cellular process that can be useful in the follow- up of the patients.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P • MYD88 mutation
26d
LPL/WM is a rare disease. Its diagnosis can be challenging due to similarities to other small B-cell lymphomas with plasmacytic differentiation and/or with IgM paraproteins. Bone marrow morphology and immunophenotype are important for diagnosis.
BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • BCL6 (B-cell CLL/lymphoma 6) • CD5 (CD5 Molecule) • MME (Membrane metallo-endopeptidase)
|
CD20 positive
26d
The patient started a treatment using CP-R [cyclophosphamide + prednisone + rituximab] with clinical improvement of the proptosis but died before ending the chemotherapy. Although plasma cell differentiation is common in MALT lymphoma, the same light chain is shared by all cells. Identifying two different monotypic light chains in separate areas suggests a composite lymphoma, here confirmed by the presence of two distinct receptor gene rearrangement patterns. The diagnosis of a second clone as Lymphoplasmocytic Lymphoma, usually associated with Waldström Macroglobulinemia, might lead to a different therapy, depending on the staging of the patient.
Clinical
|
CD5 (CD5 Molecule)
|
Rituxan (rituximab) • prednisone
27d
During study participation extensive neurological testing and serum IgM and anti MAG testing will be performed. In total 40 patients will be included and the MAGNAZ study expects to start in Q4 2021.
Clinical • P2 data
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD19 (CD19 Molecule)
|
CXCR4 mutation • CD19 mutation • MYD88 mutation + CXCR4 mutation
|
Brukinsa (zanubrutinib)
29d
For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.
Review • Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation + CXCR4 mutation
|
Venclexta (venetoclax) • Rituxan (rituximab) • ibrutinib • pirtobrutinib (LOXO-305) • mavorixafor (X4P-001) • MK-1026
30d
Clinical • New P1 trial
|
CD19 (CD19 Molecule)
|
NKX019
1m
WM/LPL appears to be composed of different subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigen selection in WM/LPL development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.
Clinical
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IGH (Immunoglobulin Heavy Locus)
|
MYD88 L265P • MYD88 mutation • MYD88 overexpression
1m
P2, N=30, Recruiting, Roswell Park Cancer Institute | Trial completion date: Jul 2022 --> Aug 2023 | Trial primary completion date: Jul 2021 --> Aug 2022
Clinical • Trial completion date • Trial primary completion date
|
HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
|
sirolimus • fludarabine IV • captisol-enabled melphalan • cyclophosphamide intravenous • mycophenolate mofetil
1m
P1/2, N=190, Recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | N=146 --> 190
Clinical • Enrollment change
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 translocation • BTK mutation • BTK C481
|
MK-1026
1m
P2, N=65, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2022 --> Aug 2021
Clinical • Enrollment closed • Trial primary completion date
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • IGH (Immunoglobulin Heavy Locus) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II)
|
Keytruda (pembrolizumab) • ibrutinib • Zydelig (idelalisib)
1m
In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory WM.
P3 data • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
Rituxan (rituximab) • ibrutinib
1m
P1a/1b, N=110, Not yet recruiting, Qilu Puget Sound Biotherapeutics (dba Sound Biologics)
Clinical • New P1 trial
|
CD20 (Membrane Spanning 4-Domains A1)
|
PSB202
2ms
P=N/A, N=55, Completed, Central Hospital, Nancy, France | Recruiting --> Completed | N=80 --> 55
Trial completion • Enrollment change
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P • MYD88 mutation
2ms
P1, N=24, Recruiting, Masonic Cancer Center, University of Minnesota | Suspended --> Recruiting
Enrollment open
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive • CD20 expression
|
GDA-201
2ms
In conclusion, Hb and β M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation
2ms
The introduction of venetoclax has lengthened the survival of patients with BTKi resistant disease. Ongoing clinical trials with promising treatment modalities such as next-generation BTKi and chimeric antigen receptor T-cell therapy have reported promising efficacy in patients with BTKi resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi resistant B-cell malignancies.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Venclexta (venetoclax)
2ms
Journal • Next-generation sequencing
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
2ms
The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib, and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. www.clinicaltrials.gov (NCT03225716).
P1 data • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
CXCR4 mutation • MYD88 mutation + CXCR4 mutation
|
ibrutinib • ulocuplumab (BMS-936564)
2ms
LCLs were immunopositive for granzyme B in 31/48 cases (65%) and CD8 in 9/48 cases (19%), while SCLs were immunopositive for granzyme B in 3/18 cases (17%) and CD8 in 3/18 cases (17%). Furthermore, 8/10 cases (80%) of ALCL and 19/27 cases (70%) of histiocyte-dominant PTCL were immunopositive for granzyme B, whereas 6/20 cases (30%) of PTCL-NOS, 1/6 cases (17%) of eosinophil-dominant PTCL, and no cases of angiotropic T-cell lymphomas were immunopositive for granzyme B. The present study describes the immunophenotypes in different histological types of transmural gastrointestinal lymphomas in the dog.
Journal
|
CD8 (cluster of differentiation 8) • PAX5 (Paired Box 5) • GZMB (Granzyme B)
2ms
Plasmapheresis followed by chemotherapy with or without the addition of rituximab resulted in improvement or normalization of the ophthalmological findings in 15 patients. The ocular manifestations of WM are protean and potentially sight threatening. Recent advances in genomic profiling and chemotherapy have remarkably improved the hematological and ophthalmological outcomes of these patients.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation
|
Rituxan (rituximab)
2ms
Zanubrutinib achieved a high rate of response that was durable and deep in R/R WM patients across all subgroups, and potentially confers a positive benefit-risk profile for WM.
Clinical • P2 data • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
Brukinsa (zanubrutinib)
2ms
In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.
Review • Journal • CAR T-Cell Therapy • IO biomarker
|
CD19 (CD19 Molecule)
3ms
Both MYD88 and CXCR4 were identified with high sensitivity and specificity in cfDNA derived from the plasma of WM patients, including previously treated patients. The use of cfDNA represents a non-invasive, convenient, and potentially cost-effective method for genotyping patients with WM.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation + CXCR4 mutation
3ms
This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.
Review • Journal
|
PLCG2 (Phospholipase C Gamma 2) • SYK (Spleen tyrosine kinase)
|
KRAS mutation
|
ibrutinib
3ms
Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (OR 0.20, 95% CI 0.05-0.73) and salvage therapy 07 days after discontinuing ibrutinib (OR 4.12, 95% CI 1.07-18.9) were identified as independent predictors of a response to salvage therapy. TP53 mutations were associated with shorter OS, while acquired BTKC481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.
Preclinical • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Rituxan (rituximab) • ibrutinib
4ms
Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses ≤400 mg QD. Unaltered mavorixafor and ibrutinib exposures suggest no apparent drug–drug interaction, and mavorixafor exposures tracked with increased WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM, suggesting mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.
Clinical data • P1 data
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P • CXCR4 mutation • MYD88 mutation • MYD88 mutation + CXCR4 mutation
|
ibrutinib • mavorixafor (X4P-001)
4ms
Results from the BiRD study confirm the sustained effectiveness of ibrutinib in both CLL and MCL. TEAEs were manageable in elderly pts with no new safety signals.
Clinical
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • IGH mutation • TP53 mutation + Chr del(17p)
|
ibrutinib
4ms
Cytotoxic potential was assessed via engagement of blinatumomab (CD3 x CD19 bi-specific T-cell engager), that re-directs T-cells via CD3 to kill CD19+ tumor cells... These data represent the first systematic evaluation of the T-cell compartment in WM. The qualitative and quantitative changes in the immune system seen in CLL are not found in WM; T-cell numbers, distribution and functionality seem mostly preserved even in pretreated patients. These findings are encouraging for application of T-cell directed immunotherapy in WM, especially for relapsed/refractory WM.
Clinical • IO biomarker
|
CD8 (cluster of differentiation 8) • CD19 (CD19 Molecule) • TNFA (Tumor Necrosis Factor-Alpha) • CD4 (CD4 Molecule) • LAMP1 (Lysosomal Associated Membrane Protein 1)
|
Blincyto (blinatumomab)
4ms
n-LPL/WM is rare, but patients usually present in advanced stages. It is easily confused with other small B-cell lymphomas with plasma cell differentiation, especially basing on morphologic features alone; thus the accurate diagnosis of n-LPL/WM requires a combination of clinical features, serum M protein, immunohistochemistry, bone marrow morphology,flow cytometry and MYD88 L265P mutation status etc. The prognosis of n-LPL/WM may be not very good, and further studies with more cases are needed.
Clinical • Journal • IO biomarker
|
CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD38 (CD38 Molecule) • SDC1 (Syndecan 1) • FCER2 (Fc Fragment Of IgE Receptor II)
|
MYD88 L265P • CD20 expression • CD38 positive • SDC1 positive
4ms
Fifty-four patients (7.3%) received monotherapy, 264 (36.0%) received chemoimmunotherapy, 395 (53.8%) received other combination regimens without rituximab, and 21 (2.9%) received ibrutinib. In summary, our study showed that frontline treatment choices for WM are widely heterogeneous. We validated most of the established prognostic factors in the rIPSS (age >65 years, LDH ≥250 IU/L, ALB <3.5 g/dl and β2 microglobulin ≥4 mg/L) together with PLT ≤ 100 × 10/L indicate a poor prognosis for patients with WM.
Retrospective data • Review • Journal
|
B2M (Beta-2-microglobulin)
|
Rituxan (rituximab) • ibrutinib
4ms
P2, N=72, Recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Apr 2021 --> Sep 2021 | Trial primary completion date: Mar 2021 --> Jul 2021
Clinical • Trial completion date • Trial primary completion date
|
FLT3 (Fms-related tyrosine kinase 3)
|
Chr del(5q)
|
fludarabine IV • thiotepa • cyclophosphamide intravenous • mycophenolate mofetil • mycophenolate sodium • tacrolimus XR • tacrolimus intravenous
4ms
Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.
Clinical • Journal
|
TP53 (Tumor protein P53) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
TP53 mutation
|
Gazyva (obinutuzumab) • Zydelig (idelalisib)
4ms
To conclude, we report the expression of CD71, CD81, CD44 and CD39 by FC in B cell lymphomas. Further studies will have to determine the value they add to specific FC panels.
Journal
|
CD44 • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1) • TFRC • MME (Membrane metallo-endopeptidase)
|
CD44 expression
4ms
P1/2, N=13, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jan 2021 --> Jan 2023
Clinical • Trial primary completion date
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation + CXCR4 mutation
|
ibrutinib • ulocuplumab (BMS-936564)
4ms
Summary: CA-4948 is a novel oral IRAK4 inhibitor of the TLR/myddosome pathway that showed preclinical synergistic activity in combination with ibrutinib. Clinical safety, tolerance, and preliminary efficacy in selected NHL cohorts are being studied.
Clinical • IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
MYD88 L265P
|
ibrutinib • emavusertib (CA-4948)
4ms
Altogether these results demonstrate for the first time that continuous MYD88 activation is specifically associated with clonal transformation of differentiating IgM B-cells. Since MYD88 targets the IgM PC differentiation continuum, it provides an interesting preclinical model for development of new therapeutic approaches to both WM and aggressive MYD88 associated DLBCLs.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule) • SDC1 (Syndecan 1) • RELA (RELA Proto-Oncogene)
|
CD19 positive • MYD88 mutation • CD19 expression
4ms
He is currently stable and under multidisciplinary monitoring. His sensory symptoms have improved following rituximab treatment and his WM is under control.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
Rituxan (rituximab)
4ms
We present the case of a 50-year-old woman found to have chylothorax secondary to progression of WM as confirmed by cytology and presence of MYD88 L265P mutation in the pleural fluid specimen and subsequent resolution with chemotherapy. This review centres particularly on non-traumatic causes of chylothorax with a focus on WM and includes a unique patient perspective.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
4ms
BTK inhibitors, ibrutinib and acalabrutinib, are highly active and may yield long-term disease control as a first-line treatment, when used in combination with rituximab in patients with IgM related AL amyloidosis and WM. Reported side effects were mild, and the treatment was well Change in dFLC Before and After BTK Inhibitor Therapy tolerated. Patients with cardiac AL amyloidosis may tolerate acalabrutinib better than ibrutinib.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
Rituxan (rituximab) • ibrutinib • Calquence (acalabrutinib)
4ms
It suppresses BCR signaling pathways (through inhibition of LYN, SYK, BTK, AKT, ERK) in cell lines and primary CLL cells, kills malignant B-cells insensitive to ibrutinib or venetoclax at low nM concentrations, and shows enhanced activity in combination with venetoclax. Pharmacodynamic studies documented inhibition of SYK, BTK and ERK in the BCR signaling pathway. Enrollment of patients with R/R CLL/SLL and NHL at dose level 5 (750 mg) is ongoing and updated clinical data will be presented at the meeting.
Clinical • P1 data
|
FLT3 (Fms-related tyrosine kinase 3) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase)
|
Venclexta (venetoclax) • ibrutinib • luxeptinib (CG-806)
4ms
Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM levels, suggesting that mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.
Clinical data • P1 data
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CXCL12 (C-X-C Motif Chemokine Ligand 12)
|
MYD88 L265P • CXCR4 mutation • MYD88 mutation • MYD88 mutation + CXCR4 mutation
|
ibrutinib • mavorixafor (X4P-001)
4ms
However, there was little impact of bleeding complications, hematological adverse effects and new cases of AF. Generally, Ibrutinib is a well-tolerated and effective drug.
Clinical • Adverse events
|
TP53 (Tumor protein P53)
|
Chr del(11q)
|
ibrutinib
4ms
Six patients (20%) had relapsed and received a second line therapy (1 FCR, 1 Chlorambucil, 1 Ibrutinib, 1 no further therapy due to extreme age, 1 patient with bi-clonal disease with CLL treated with Idelalisib and Rituximab and 1 moved to another institution). The overall survival in this study was 65% at 36 months and evaluating the MYD88 mutational status impact was limited due the small sample size and retrospective nature of this study. CXCR4 mutation screening for this study cohort is in progress and longer follow up will continue prospectively.
Clinical
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P • CXCR4 mutation • MYD88 mutation
|
Rituxan (rituximab) • ibrutinib • Zydelig (idelalisib) • Leukeran (chlorambucil)
4ms
Similar patterns of response with IR were observed in pts receiving first-line treatment and in previously treated pts. No new safety signals were observed; IR maintained a manageable safety profile after an additional 24 months of follow-up.
Clinical • P3 data
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P • MYD88 mutation
|
Rituxan (rituximab) • ibrutinib
4ms
Furthermore, cytotoxic potential of the T-cells was assessed via engagement of blinatumomab (CD3xCD19 bi-specific T-cell engager), that re-directs T-cells via CD3 to kill CD19+ tumor cells...The qualitative and quantitative changes in the immune system seen in CLL are not found in WM; T-cell numbers, distribution and functionality seem mostly preserved even in pretreated patients with a high disease burden. These findings are encouraging for the application of T-cell targeted immune therapies in WM, especially for the management of relapsed/refractory WM.
Clinical • IO biomarker
|
CD8 (cluster of differentiation 8) • CD19 (CD19 Molecule) • TNFA (Tumor Necrosis Factor-Alpha) • CD4 (CD4 Molecule) • LAMP1 (Lysosomal Associated Membrane Protein 1)
|
Blincyto (blinatumomab)
4ms
Conclusion Results over a median follow-up of 35+ months from the BiRD study confirm the sustained effectiveness of ibrutinib in both CLL and MCL. TEAEs were manageable in elderly patients with no new safety signals.
Clinical
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • IGH mutation • TP53 mutation + Chr del(17p)
|
ibrutinib
4ms
BTK inhibitors have been widely studied in B-cell hematologic malignancies and 3 inhibitors, including the first-in-class BTK inhibitor ibrutinib, are currently approved. Conclusion The preclinical results confirm that JNJ-64264681 is a highly selective and potent BTK inhibitor and provide proof-of-concept for human trials in patients with B cell malignancies driven by the classical NF-κB pathway. JNJ-64264681 is currently in human clinical trials (NCT04210219 and NCT04657224) as single agent to establish dose and pharmacokinetics and to evaluate efficacy in combination with the first-in-class MALT1 inhibitor JNJ-67856633.
Preclinical
|
CD79B (CD79b Molecule) • MALT1 (MALT1 Paracaspase)
|
CD79B mutation • CD79B mutation
|
ibrutinib • JNJ-67856633 • JNJ-64264681
4ms
CIT comprised 6 cycles of intra- venous rituximab 375 mg/m2, intravenous cyclophosphamide 750 mg/m2, and oral prednisolone 50 mg/m2 (days 1 to 5) every 21 days. The literature evidence at present suggests a link is more likely to be due to shared epidemiological risk factors, genetic predisposition or common pathophysiologic pathways. Therefore, although a direct causal link between use of immunosuppression and GBM is unlikely, we suggest clinicians be cautious about use of CIT in this specific patient group.
IO biomarker
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IL2RA (Interleukin 2 receptor, alpha)
|
IDH1 mutation
|
Rituxan (rituximab) • prednisolone • cyclophosphamide intravenous
4ms
Previous data.2,3 has indicated that patients on BTK inhibitors may be at particular risk of developing invasive intracerebral aspergillosis. Further clinical and molecular data and genomic analysis could be considered to better understand these recent cases of intracerebral aspergillosis within a localised area, and to risk-stratify patients who may require prophy- lactic antifungal treatment.
Clinical
|
NFATC1 (Nuclear Factor Of Activated T Cells 1)
|
ibrutinib • Cresemba (isavuconazonium sulfate)
5ms
P3, N=202, Active, not recruiting, University of Ulm | Trial completion date: Sep 2023 --> Apr 2024
Clinical • Trial completion date
|
CD20 (Membrane Spanning 4-Domains A1) • CD19 (CD19 Molecule) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II) • MME (Membrane metallo-endopeptidase)
|
CD20 positive • CD5 positive
|
Rituxan (rituximab) • bortezomib • dexamethasone • cyclophosphamide intravenous
5ms
Clinical • Enrollment change • Trial termination
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
|
Rituxan (rituximab) • bortezomib • Torisel (temsirolimus) • Decadron (dexamethasone)
5ms
P1/2, N=24, Completed, Alexey Danilov, MD | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Apr 2021 | Trial primary completion date: Feb 2022 --> Apr 2021
Clinical • Trial completion • Trial completion date • Trial primary completion date • Combination therapy
|
CCND1 (Cyclin D1) • FCER2 (Fc Fragment Of IgE Receptor II)
|
CCND1 overexpression
|
Gazyva (obinutuzumab) • entospletinib (GS-9973)
5ms
In conclusion, we showed the deregulation of groups of genes belonging to KEGG pathways in the comparison among WM vs. IgM MGUS vs. CTRLs in B-cells. Interestingly, a small set of genes in B-cells displayed a common transcriptome expression profile between WM and IgM MGUS compared to CTRLs, suggesting its possible role in the risk of transformation of IgM MGUS to WM.
Journal
|
CD19 (CD19 Molecule) • SDC1 (Syndecan 1)
|
CD19 expression
5ms
Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
5ms
On the other hand, our results showed that MYD88 detection on PB samples, especially with ASqPCR, is suboptimal for screening and MRD analysis. Finally, significantly different MYD88 mutational levels observed between Waldenström Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance patients suggest the need for further studies in order to identify possible correlations between mutational levels and risk of progression to Waldenström.
Journal • Tumor Mutational Burden
|
TMB (Tumor Mutational Burden) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule)
|
TMB-L • MYD88 mutation
5ms
Clinical • Trial completion
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
|
Rituxan (rituximab) • bortezomib • dexamethasone injection
5ms
However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IGH (Immunoglobulin Heavy Locus)
|
MYD88 L265P
5ms
We evaluated three commonly used frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naïve patients with WM, seen at Mayo Clinic between 11/01/2000 and 10/31/2019. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88 mutation status.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
Rituxan (rituximab) • bortezomib • bendamustine
5ms
P3, N=184, Recruiting, Christian Buske | Not yet recruiting --> Recruiting | Trial completion date: Sep 2027 --> Feb 2028 | Trial primary completion date: Sep 2027 --> Feb 2028
Clinical • Enrollment open • Trial completion date • Trial primary completion date • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD19 (CD19 Molecule) • CD38 (CD38 Molecule) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II) • MME (Membrane metallo-endopeptidase)
|
CD20 positive • CD5 positive
|
ibrutinib • carfilzomib
5ms
P1/2, N=46, Terminated, Dana-Farber Cancer Institute | Active, not recruiting --> Terminated; Per protocol, Phase II is to be terminated early if a less than 5% of the Phase II participants observe a Very Good Partial Response or Better in the first 23 participants enrolled to Phase II.
Clinical • Trial termination
|
PTEN (Phosphatase and tensin homolog) • CD20 (Membrane Spanning 4-Domains A1)
|
PTEN mutation • CD20 positive
|
Rituxan (rituximab) • everolimus • bortezomib
5ms
P=N/A, N=300, Active, not recruiting, Fondazione Italiana Linfomi ONLUS | Trial primary completion date: Jun 2021 --> Oct 2020
Trial primary completion date • Minimal residual disease
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P • MYD88 mutation • CXCR4 S338X
5ms
P=N/A, N=300, Active, not recruiting, Fondazione Italiana Linfomi ONLUS | Recruiting --> Active, not recruiting
Enrollment closed • Minimal residual disease
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P • MYD88 mutation • CXCR4 S338X
6ms
Although a causal relation cannot be definitively proved, the number of cases reported suggests that there might be an association. Increased awareness of these risks among healthcare professionals may help to reduce the number and early identification of adverse events.
Adverse events
|
ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
|
ibrutinib
6ms
Clinical • Enrollment closed
|
CD19 (CD19 Molecule)
|
CD19 positive
|
etoposide IV • fludarabine IV • CD19 CAR T cells • cyclophosphamide intravenous
6ms
Clinical • Enrollment open
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • CD4 (CD4 Molecule)
|
BCL6 rearrangement • BCL2 rearrangement
|
Rituxan (rituximab) • doxorubicin hydrochloride • vincristine • Onureg (azacitidine oral) • cyclophosphamide intravenous • prednisone delayed-release tablet
6ms
Clinical • New P1 trial
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • CD4 (CD4 Molecule)
|
BCL6 rearrangement • BCL2 rearrangement • BTK C481
|
NX-2127
6ms
Glycosylation of LCs was significantly more common in IgM amyloid patients compared to patients with non-AL IgM gammopathies (21% vs. 7%, p=0.001). This is similar to observations in all patients with AL amyloidosis.
Clinical
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
6ms
Additionally, initial treatment with rituximab or bortezomib significantly improved the PFS and OS of CD4/CD8 inversion patients but did not affect normal CD4/CD8 patients. We show that low circulating CD4/CD8 ratio at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy which included rituximab or bortezomib significantly improved PFS and OS for patients with CD4/CD8 ratio less than 1.5.
Clinical • Journal
|
CD8 (cluster of differentiation 8) • B2M (Beta-2-microglobulin) • CD4 (CD4 Molecule)
|
Rituxan (rituximab) • bortezomib
6ms
Taken together, these findings indicate that an FHL2 mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases.
Journal
|
IL6 (Interleukin 6)
6ms
Our findings show that MCL with plasmacytic differentiation can cause amyloid deposition and CCND1 abnormalities should be performed in all cases of extramedullary AL amyloidosis. Recognition of indolent MCL as a cause of peritumoral AL amyloidosis may have important clinical management implications.
Journal
|
CCND1 (Cyclin D1) • SOX11 (SRY-Box Transcription Factor 11)
|
CCND1 expression
6ms
Although rare, Waldenström Macroglobulinemia and IgM gammopathy are responsible for diverse manifestations of renal disease. A prompt diagnosis is of utmost importance in order to ensure early start of therapy, which should be directed at the underlying hematologic disorder, to improve renal survival.
CD20 (Membrane Spanning 4-Domains A1)
6ms
Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM...Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival...In conclusion, genetic testing for MYD88, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
Clinical • Journal • Next-generation sequencing
|
TP53 (Tumor protein P53) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
TP53 mutation • CXCR4 mutation • MYD88 mutation
|
Rituxan (rituximab) • ibrutinib • dexamethasone
6ms
Clinical • New P2/3 trial
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6) • CD4 (CD4 Molecule)
|
BCL6 rearrangement • BCL2 rearrangement
|
Rituxan (rituximab) • doxorubicin hydrochloride • vincristine • Onureg (azacitidine oral) • cyclophosphamide intravenous • prednisone delayed-release tablet
6ms
There was no statistical difference between LEF1 expression and the OS and PFS in LBL/ALL patients. Immunohistochemical staining of LEF1 has high sensitivity and good specificity in the diagnosis of LBL/ALL, and its combination with TdT can improve the diagnostic rate of LBL/ALL.
Journal
|
LEF1 (Lymphoid Enhancer Binding Factor 1)
6ms
Both CD19 selection and AS-PCR markedly improved detection of CXCR4 mutations. Sensitivity was adversely impacted by low BM involvement and CXCR4 mutation clonality.
Journal • Next-generation sequencing
|
CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD19 (CD19 Molecule)
|
CXCR4 mutation • CXCR4 S338X
|
ibrutinib • Brukinsa (zanubrutinib)
7ms
WM patients who progress after achieving major responses on the newest drug (ibrutinib) acquire mutations in other genes, yet keep the MYD88 L265P intact, underscoring the unmet clinical need of targeting MYD88 L265P...Several compounds significantly reduce the viability of lymphoma cells with MYD88 L265P, but not those with WT MYD88; and they inhibit the ubiquitination of MYD88 L265P. Thus, MYD88 L265P mutation elicits a neo-biochemical reaction that can be exploited by AI-based drug development to address the unmet clinical need of targeting an "undruggable" oncoprotein.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
|
ibrutinib
7ms
In summary, our data show that reduced fatty acid and lipid metabolite levels in the serum of the WM patients are associated with increased lipid peroxidation and that downregulation of 15-LOX increases the survival of WM cells. These data are highly significant in identifying the biomarkers of disease progression and designing targeted therapeutic intervention.
Journal
|
IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • GPX4 (Glutathione Peroxidase 4)
7ms
Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.
Review • Journal • IO biomarker
|
BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD8 (cluster of differentiation 8) • BCL6 (B-cell CLL/lymphoma 6) • CD4 (CD4 Molecule) • TP63 (Tumor protein 63)
|
BRAF V600E • BRAF V600 • MYD88 L265P • BCL2 expression • MYC expression • BCL6 rearrangement • CD8 positive • BCL2 rearrangement • MYD88 L265P + BRAF V600E • CD4 positive
7ms
VS38 identified neoplastic cells in plasma cell disorders and BCL. This might improve the accuracy of BCL diagnosis, especially in patients with LPL/WM.
Journal • IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD27
|
MYD88 L265P
7ms
Thus, up to 40% of all patients with Waldenström's macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Bruton's tyrosine kinase inhibitor ibrutinib...Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM cell behaviour, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.
Journal
|
CXCL12 (C-X-C Motif Chemokine Ligand 12)
|
CXCR4 mutation
|
ibrutinib
7ms
Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P • MYD88 mutation
|
Rituxan (rituximab) • ibrutinib • Revlimid (lenalidomide) • everolimus • bortezomib • carfilzomib • thalidomide • bendamustine • fludarabine IV
7ms
FCM exploration of both B-cells and PC led to identify a CD138 expression continuum as an objective marker of ongoing PC differentiation of WM tumor cells and was strongly associated with increased IgM peak levels and MYD88 mutations. This approach could contribute to place FCM at the forefront of WM diagnosis.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • SDC1 (Syndecan 1)
|
CXCR4 mutation • MYD88 mutation • MYD88 mutation + CXCR4 mutation
7ms
These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.
Review • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 positive
|
ibrutinib
7ms
P2, N=68, Recruiting, Mayo Clinic | Trial completion date: Jan 2022 --> Jan 2023 | Trial primary completion date: Jan 2021 --> Jan 2022
Clinical • Trial completion date • Trial primary completion date
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • IGH (Immunoglobulin Heavy Locus) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II)
|
Keytruda (pembrolizumab) • ibrutinib • Zydelig (idelalisib)
7ms
Zanubrutinib has resulted in clinically meaningful antitumor activity, including deep and durable responses, with a low discontinuation rate due to treatment-related toxicities. Combination regimens and non-covalent BTK inhibitors are emerging as promising treatment strategies. Long-term data will determine whether next-generation BTK inhibitors are more potent and safer compared with ibrutinib, and whether they are able to overcome resistance to ibrutinib, either alone or in combination with inhibitors of other interrelated molecular pathways.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
ibrutinib • Brukinsa (zanubrutinib)
7ms
P1, N=15, Recruiting, City of Hope Medical Center | Trial primary completion date: Jan 2021 --> Dec 2022
Clinical • Trial primary completion date • Combination therapy
|
PD-L1 (Programmed death ligand 1)
|
Opdivo (nivolumab) • Aliqopa (copanlisib)
7ms
In this review, we describe how current genomics may be utilized to optimize WM treatment selection. As the therapeutic landscape of WM continues to expand with more targeted approaches, the genomics in WM will likely play a greater role in individualizing treatment.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
7ms
P1/2, N=146, Recruiting, ArQule | Trial completion date: Nov 2022 --> Sep 2022 | Trial primary completion date: Nov 2022 --> Sep 2022
Clinical • Trial completion date • Trial primary completion date
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 translocation • BTK mutation • BTK C481
|
MK-1026
8ms
Even in patients with advanced age and at high risk of ISSWM, the overall remission rate and major remission rate are high. Ibrutinib is a safe and effective therapy because of its rapid onset and rare serious adverse reactions.
Clinical data • Retrospective data • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
|
ibrutinib
8ms
P2, N=135, Recruiting, Fred Hutchinson Cancer Research Center | Trial completion date: Dec 2023 --> Jun 2025 | Trial primary completion date: Dec 2022 --> Jun 2023
Clinical • Trial completion date • Trial primary completion date
|
HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
|
fludarabine IV • thiotepa • cyclophosphamide intravenous • cyclosporin A microemulsion • mycophenolate mofetil
8ms
P1, N=24, Suspended, Masonic Cancer Center, University of Minnesota | Recruiting --> Suspended
Clinical • Trial suspension
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive • CD20 expression
|
GDA-201
8ms
This translated in increased and more sustained production of antibodies upon T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.
Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MTOR mutation
8ms
P1, N=30, Recruiting, Bio-Path Holdings, Inc. | Trial completion date: Aug 2021 --> Aug 2022 | Trial primary completion date: Feb 2021 --> Feb 2022
Clinical • Trial completion date • Trial primary completion date • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 expression
|
liposomal Bcl2 (BP1002)
8ms
P1, N=4, Terminated, University of Michigan Rogel Cancer Center | N=26 --> 4 | Trial completion date: Sep 2021 --> Jul 2020 | Recruiting --> Terminated | Trial primary completion date: Sep 2021 --> Mar 2020; Low accrual
Clinical • Enrollment change • Trial completion date • Trial termination • Trial primary completion date
|
JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • JAK3 (Janus Kinase 3) • TYK2 (Tyrosine Kinase 2) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1)
|
JAK3 mutation
|
Enpaxiq (pacritinib)
8ms
Fortunately, there is a variety of approved therapeutic option in previously untreated WM patients, based on either an alkylating agent, proteasome inhibitor, bendamustine, rituximab-alone, or ibrutinib. In this talk, I will discuss current chemo-immunotherapeutic (CIT) regimens versus ibrutinib treatment, as well as second generation BTK-inhibitors. I will also present new data coming from ASH 2020, portraying future directions in the treatment of WM.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation
|
Rituxan (rituximab) • ibrutinib • bendamustine
8ms
P2, N=134, Not yet recruiting, Academic and Community Cancer Research United | Initiation date: Dec 2020 --> Jun 2021
Clinical • Trial initiation date
|
IL6 (Interleukin 6) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2) • IL10 (Interleukin 10) • CD4 (CD4 Molecule) • IL1B (Interleukin 1, beta)
|
ibrutinib
8ms
Patients with Schnitzler syndrome also exhibit IgM monoclonal gammopathy, and 15-20% of patients eventually develop a lymphoproliferative disorder resembling Waldenström macroglobulinemia with an MYD88 mutation. At present, the precise pathogenesis of Schnitzler syndrome remains unknown.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
9ms
P1/2, N=20, Terminated, Northwestern University | N=33 --> 20 | Active, not recruiting --> Terminated; Lack of funding
Clinical • Enrollment change • Trial termination
|
CD20 (Membrane Spanning 4-Domains A1) • TNFRSF8 (TNF Receptor Superfamily Member 8)
|
CD20 expression
|
Rituxan (rituximab) • Adcetris (brentuximab vedotin)
9ms
Conclusions In our cohort rash, cardiac arrythmia and diarrhoea were the most clinically significant side effects. It is important to manage these side effects appropriately and use dose modifications to allow patients to gain maximum disease control with Ibrutinib.
Clinical • Real-world evidence
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
ibrutinib
9ms
The patient received six courses of rituximab, cladribine and dexamethasone, and a repeat bone marrow assessment showed reduction in the both clones but both were still detectable (LPL ˜7% and HCL ˜2%) respectively. Co‐existent LPL and HCL have not been reported in the literature so far to the best of our knowledge. Keywords: Synchronous dual haematological malignancy (SDHM), bone marrow (BM), lymphoplasmacytic lymphoma (LPL), Hairy cell leukaemia (HCL), polymerase chain reaction (PCR)
BRAF (B-raf proto-oncogene) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD38 (CD38 Molecule) • IL2RA (Interleukin 2 receptor, alpha) • CD123 (Interleukin 3 Receptor Subunit Alpha) • SDC1 (Syndecan 1)
|
BRAF V600E • BRAF V600 • MYD88 L265P
|
Rituxan (rituximab) • cladribine • dexamethasone
9ms
Alternative frontline regimens included R‐CVP (n = 4), R‐CHOP (n = 1) and R‐Bendamustine (n = 1)...Two patients had Bing‐Neel Syndrome and the third was frail and relapsed following first line Rituximab and Chlorambucil...Indeed, some unfit patients declined chemoimmunotherapy or were offered symptomatic management only. It is clear that many of these patients may have benefited from Ibrutinib and there will no doubt be an increase in Ibrutinib use going forward in this patient group.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
Rituxan (rituximab) • ibrutinib • bendamustine • Leukeran (chlorambucil)
9ms
Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • ARID1A (AT-rich interaction domain 1A) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD79B (CD79b Molecule) • NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1)
|
CXCR4 mutation • MYD88 mutation
|
ibrutinib
9ms
Materials & WM cells were treated with BET inhibitors (JQ-1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
Venclexta (venetoclax) • ibrutinib • JQ-1 • Farydak (panobinostat) • molibresib (GSK525762)
9ms
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BCL6 (B-cell CLL/lymphoma 6)
|
MYD88 L265P
9ms
The success of the first-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has generated tremendous interest in the study of more selective and potent BTK inhibitors. Additionally, the identification of CXCR4 mutations in up to approximately 40% of patients with WM has fueled research regarding their implication on systemic therapy in WM. In a rapidly advancing field of targeted therapies, the treatment options for patients with WM are expanding as researchers continue to uncover and harness the survival pathways active in this hematologic malignancy.
Review • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
CXCR4 mutation • MYD88 mutation
|
ibrutinib
9ms
In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88 mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule)
|
CD19 positive • MYD88 L265P • MYD88 mutation
9ms
P1, N=30, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2020 --> Oct 2021 | Trial primary completion date: Oct 2020 --> Oct 2021
Clinical • Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor) • CD19 (CD19 Molecule) • CD34 (CD34 molecule)
|
peripheral blood stem cell transplantation
9ms
The patient was treated with high-dose intravenous steroids and cyclophosphamide. The treatment showed that the skin lesions had improved, pain disappeared and motor deficit stopped its progression.
Journal
|
CRP (C-reactive protein)
|
cyclophosphamide intravenous
10ms
Zanubrutinib also has a favorable toxicity profile when compared to Ibrutinib. This may potentially translate to lower discontinuation rates, improved quality of life and ultimately longer progression-free survival in patients with WM.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
ibrutinib • Brukinsa (zanubrutinib)
10ms
Clinical • New P2 trial
|
IL6 (Interleukin 6) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2) • IL10 (Interleukin 10) • CD4 (CD4 Molecule) • IL1B (Interleukin 1, beta)
|
ibrutinib
10ms
Clinical • Enrollment open
|
HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1)
|
fludarabine IV • busulfan • Ovastat (treosulfan) • Neupogen (filgrastim) • cyclophosphamide intravenous • cyclosporin A microemulsion • mycophenolate mofetil • mycophenolate sodium
10ms
Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study...Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.
P3 data • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 mutation
|
ibrutinib • Brukinsa (zanubrutinib) • enoxaparin sodium
10ms
Clinical • Enrollment open
|
CD20 (Membrane Spanning 4-Domains A1) • CD4 (CD4 Molecule)
|
Revlimid (lenalidomide) • Gazyva (obinutuzumab) • Onureg (azacitidine oral)
10ms
Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P
|
Venclexta (venetoclax) • Rituxan (rituximab) • ibrutinib • bortezomib • Ninlaro (ixazomib) • Calquence (acalabrutinib) • Brukinsa (zanubrutinib) • carfilzomib • Arzerra (ofatumumab) • bendamustine • pirtobrutinib (LOXO-305) • mavorixafor (X4P-001) • ulocuplumab (BMS-936564) • MK-1026 • Velexbru (tirabrutinib) • cyclophosphamide intravenous • vecabrutinib (SNS-062)
10ms
P1, N=9, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2020 --> Feb 2023 | Trial primary completion date: Feb 2020 --> Feb 2022
Clinical • Trial completion date • Trial primary completion date
|
CD20 (Membrane Spanning 4-Domains A1)
10ms
Cutaneous involvement by LPL can histologically mimic other, established entities, but can be recognised and confirmed by molecular testing methods. Its stable persistence over one year suggests relatively indolent clinical behaviour.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
10ms
While the management of large lesions utilizes localized radiation, an observatory strategy can be employed for smaller lesions, as was done in this case. Treatment with systemic chemotherapy is reserved for extra-cutaneous involvement.
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
10ms
Co-cultures of natural killer cells and cells from a WM cell line further suggest that both factors participate in immune evasion by promoting escape from natural killer cell-mediated cytotoxicity. Together, the interplay of BLIMP1 and EZH2 plays a vital role in promoting the survival of WM cell lines, suggesting a role for the two factors in Waldenström's macroglobulinaemia.
Journal
|
EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
10ms
He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy...After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
Chr t(11;14)
|
carfilzomib
10ms
To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.
Clinical • Journal
|
CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • FLCN (Folliculin) • SDC1 (Syndecan 1)
|
CD20 positive • FLCN mutation • SDC1 positive
10ms
The rituximab, cliclophosphamide and dexamethasone (RDC) regimen proves to be highly effective and well tolerated, being considered first-line treatment, despite the average time for disease control. Involvement in young individuals makes diagnosis difficult due to little clinical suspicion. The patient is preferentially affected outside the age range, diagnosed as a finding after a fall, started treatment initially with a double regimen and, subsequently, complete RDC.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • BCL6 (B-cell CLL/lymphoma 6) • TNFRSF8 (TNF Receptor Superfamily Member 8) • CD19 (CD19 Molecule) • B2M (Beta-2-microglobulin) • CD5 (CD5 Molecule) • SDC1 (Syndecan 1)
|
CD20 positive
|
Rituxan (rituximab) • cyclophosphamide intravenous
10ms
After diagnosis of ALL / Burkitt patient, even with negative COVID PCR, he was kept in isolation according to the local hospital protocol, but allocated in a single room. Chose to start GMALL protocol right after leaving isolation.
Clinical
|
CD20 (Membrane Spanning 4-Domains A1) • CD19 (CD19 Molecule)
10ms
Although no standard treatment has yet been established, patients with BNS harboring the MYD88 L265P mutation have been reported to respond favorably to ibrutinib, which can cross the blood-brain barrier and trigger apoptosis of MYD88 L265P-positive LPCs...Persistent MRD increased 2 weeks before the onset of relapse symptoms without any abnormal imaging findings or evidence of clonal LPCs on CSF cytology, flow cytometry analysis, or immunofixation electrophoresis. Our findings suggest that an increase in MRD levels is correlated with relapse in patients with BNS.
Clinical • Journal • Polymerase Chain Reaction
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
|
ibrutinib
10ms
Cotreatment of JH-X-119-01 with the BTK inhibitor ibrutinib resulted in synergistic killing effects in these systems. Taken together, JH-X-119-01 represents a highly selective probe of IRAK1 for further development.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
ibrutinib
10ms
MYD88 L265P mutation is seen in various B-cell neoplasms; it is most commonly seen in LPL/WM cases but not specific for it.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
10ms
Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • FGFR (Fibroblast Growth Factor Receptor) • NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SYK (Spleen tyrosine kinase)
10ms
This indicated a diagnosis of ocular adnexal Waldenström Macroglobulinemia. This case highlights the importance of clinical evaluation, histopathology, and immunohistochemistry for phenotyping of ocular adnexal lymphomas.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • CD5 (CD5 Molecule) • IRF4 (Interferon regulatory factor 4)
11ms
Our MYD88 L265P ddPCR assay validation showed excellent accuracy, reproducibility, specificity, and a maximal reproducible sensitivity of 0.1%FA. This assay shows promising clinical applications, especially in the setting of primary CNS lymphoproliferative disorders, and provides further insights into the role of MYD88 L265P in CNS-LPDs arising in immunocompetent and immunocompromised individuals.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
11ms
This conference is advantageous since it promotes remote participation by physicians from the satellite offices and non-academic centers. MPS resulted in refinement of the final diagnosis in a significant number of cases, thereby impacting clinical management. Our experience indicates that this tumor board provides an opportunity to develop practice guidelines for MPS testing, promote accurate diagnoses of lymphoproliferative disorders, educate multidisciplinary audiences on precision medicine principles, and develop opportunities for research.
IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CREBBP (CREB binding protein) • NOTCH2 (Notch 2) • TNFAIP3 (TNF Alpha Induced Protein 3) • GNA13 (G Protein Subunit Alpha 13)
|
IDH2 mutation • GNA13 mutation
11ms
Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.
Journal
|
PTEN (Phosphatase and tensin homolog) • BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • BIRC3 (Baculoviral IAP repeat containing 3) • CARD11 (Caspase Recruitment Domain Family Member 11) • PLCG2 (Phospholipase C Gamma 2) • NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) • TNFAIP3 (TNF Alpha Induced Protein 3)
|
PLCG2 mutation
|
Venclexta (venetoclax) • ibrutinib • Xpovio (selinexor) • Zydelig (idelalisib)
11ms
They do not necessarily represent high-grade transformation. This small yet comprehensive series suggests they constitute a hitherto undescribed novel indication for systemic therapy irrespective of the general disease status.
CD20 (Membrane Spanning 4-Domains A1) • SDC1 (Syndecan 1)
11ms
These encouraging results provide clinical validation of IRAK4 as a viable, novel therapeutic target in B-cell malignancies will lead to clinical combinations with synergistic drugs including BTK or BCL2 inhibitors &lsqb;3] in patients with advanced hematological malignancies. Clinical trial: NCT03328078.
Clinical • P1 data • PK/PD data • IO biomarker
|
IL1R1 (Interleukin 1 receptor, type I)
|
emavusertib (CA-4948)
11ms
Interestingly, although not significant, IgM-MM had lower transcript levels of BCL-XL and MCL-1 compared to non-IgM-t(11;14)-MM, believed to be a predictor of higher sensitivity to venetoclax, and therefore an important guide for treatment choice. Clinical data however is lacking, and further investigations are needed to fully understand the potential role of these drugs in treating IgM-MM. In summary we describe a unique genomic and transcriptomic profile of IgM-MM, compared to both non-IgM-MM and WM, that describes its cellular origin and provides the rationale for potential therapeutic intervention.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • IGH (Immunoglobulin Heavy Locus) • BCL2L1 (BCL2-like 1) • PAX5 (Paired Box 5)
|
Chr t(11;14)
|
Venclexta (venetoclax)
11ms
Dose escalated etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone with rituximab (DA-EPOCH-R) is effective in aggressive large B cell lymphomas including de novo DLBCL, Burkitt lymphoma, high grade B cell lymphoma with BCL2-Myc rearrangement and primary mediastinal B cell lymphoma...Despite this, DA-EPOCH-R treated T-DLBCL has outcomes comparable to de novo DLBCL. Large, prospective studies are needed to examine efficacy of DA-EPOCH-R in T-DLBCL.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
MYC rearrangement + BCL2 rearrangement • MYC rearrangement • BCL2 rearrangement
|
Rituxan (rituximab) • doxorubicin hydrochloride • etoposide IV • prednisone • vincristine • cyclophosphamide intravenous
11ms
PN is frequently the sole indication for treatment, reflecting this. Clinical improvement or stabilisation was seen in 75% of treated patients, and attainment of ≥50% reduction in IgM (PR) and treatment with rituximab is associated with a more favourable outcome, whereas AL amyloid neuropathy appears to be more treatment resistant.
B2M (Beta-2-microglobulin)
|
MYD88 L265P
|
Rituxan (rituximab)
11ms
Conclusions : Zanubrutinib was shown to be highly active in patients with R/R WM, as demonstrated by a high MRR, ≥VGPR rate. Zanubrutinib was generally well tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies.
Clinical • P2 data
|
EGFR (Epidermal growth factor receptor)
|
Brukinsa (zanubrutinib)
11ms
This technology is particularly interesting as it can be applied in the plasma cfDNA from the peripheral blood of patients where the amounts of DNA are especially low. Furthermore it represents a cost-effective sensitive tool avoiding the use of costly instruments such as digital droplet PCR accompanied with costly consumables which makes it hard to use for everyday screening.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule)
|
MYD88 L265P
11ms
Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Time-to-event endpoints will be summarized by median and corresponding 95% CI using the Kaplan–Meier method. The study is actively accruing patients at sites across North America, Europe, and Asia-Pacific.
Clinical • P2 data
|
CD20 (Membrane Spanning 4-Domains A1)
|
odronextamab (REGN1979) • T-cell receptor therapy
11ms
Importantly, we assessed MYD88-mRNA expression using harvested bone marrow femurs; and found a significant reduction of MYD88- and MYD88-downstream target HCK in NSC12-treated mice was confirmed ex vivo (P<0.05). Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88.
FGFR3 (Fibroblast growth factor receptor 3) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule) • FGFR (Fibroblast Growth Factor Receptor) • NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) • FGF2 (Fibroblast Growth Factor 2) • SYK (Spleen tyrosine kinase)
|
CD19 positive
11ms
We show for the first time that WM patients have somatic mutations, including MYD88L265P and CXCR4 at the B cell progenitor level. Taken together, this study suggests that in some patients, WM could develop from B cell clones carrying MYD88L265P rather than being the initiating event, and that other mutations or CNA are required for the expansion of B cells and PCs with the WM phenotype.
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD34 (CD34 molecule) • SDC1 (Syndecan 1)
|
BRAF V600E • BRAF V600 • MYD88 L265P • CXCR4 mutation • MYD88 mutation
11ms
Beside Rituximab-Bendamustine the combination Dexamethasone, Rituximab and Cyclophospamide (DRC) is the most widely recommended immunochemotherapy in national and international guidelines based on its low myelotoxicity and anti-lymphoma activity in WM... This is the first and largest prospective randomized trial to evaluate bortezomib in combination with standard immunochemotherapy, demonstrating that B-DRC is a well-tolerated regimen which induces a high rate of major responses including deep remissions after 6 months of treatment with a 2-year PFS of 81%, independently of the mutational status of MYD88 and CXCR4. At this time point of analysis, adding Bortezomib to DRC did not induce significant differences in PFS compared to DRC alone. Future trials will have to compare chemotherapy-free approaches such as continuous treatment with BTK inhibitors with fixed duration treatments exemplified by B-DRC to understand which of the two treatment approaches offers the highest long - term sustained clinical benefit to WM patients.
Clinical • P2 data • Combination therapy
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 mutation
|
Rituxan (rituximab) • bortezomib • cyclophosphamide oral • dexamethasone • bendamustine
11ms
Preliminary results of serial single cell RNAseq analysis suggest that the tumor immune microenvironment is favorably altered after chemokine-tumor antigen DNA vaccine treatment and these vaccine-induced changes may correlate with clinical outcome. The immunologic changes observed suggest response to this vaccine, and warrant further investigation in a Phase II trial, possibly in combination with immune checkpoint blockade.
Clinical • IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P
11ms
However, the median immunoglobulin M (IgM) was substantially lower in patient’s treated with ibrutinib (2,570 mg/dL [range: 422-9,001 mg/dL]) and single-agent rituximab (R), 2,855 mg/dL (range: 84-7,880 mg/dL) when compared to those treated with chlorambucil +/- rituximab (4,416 mg/dL [range: (9-8,130 mg/dL]) and bortezomib/dexamethasone +/- rituximab (BDR), 4,086 mg/dL (range: 16-9,944 mg/dL). MYD88 testing occurred in 40 (13%) of patients, with testing most frequently occurring in patients treated with bendamustine +/- rituximab (BR), ibrutinib, and BDR- likely reflecting increased adoption in later periods...Limitations of this study include the differences observed in follow-up time as well as the limited number of patients in some 1L treatment groups. Further research is required to establish the long-term benefits and potential treatment-related toxicities of WM treatments in real-world clinical settings.
Clinical • Clinical data
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
Rituxan (rituximab) • ibrutinib • bortezomib • cyclophosphamide oral • dexamethasone • bendamustine • Leukeran (chlorambucil)
11ms
Conclusions : Our active prospective screening approach to identify familial predisposition to PCDs revealed that 11.3% of patients had families with at least one additional affected member and some families had a substantially higher incidence of PCDs with earlier onset. Study of these high-risk families have identified genomewide association markers which in future may help us define familial predisposition to plasma cell dyscrasias.
Clinical
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
11ms
Sixty-two patients were treated, at front-line 60% received rituximab-based therapy and 39% monotherapy...Further studies are needed to better delineate this sub-group of patients and explore its pathogenesis. Studying medullary cytokinic environment, WM cells, tumoral microenvironment and M paraprotein contributions could elucidate the underlying pathophysiological mechanisms involved.
Retrospective data
|
TP53 (Tumor protein P53) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CRP (C-reactive protein)
|
TP53 mutation • MYD88 L265P • CXCR4 mutation
|
Rituxan (rituximab)
11ms
Various treatments that appear to cross the blood-brain barrier are used, including chemoimmunotherapy combinations and Ibrutinib. High-dose methotrexate (HDM)-based regimens, including MATRix (methotrexate [MTX], cytarabine, thiotepa, rituximab)1and R-IDARAM (rituximab, MTX [intrathecal and intravenous], cytarabine, dexamethasone) are also used, based on the experience in high-grade CNS lymphoma; however, there are concerns regarding the appropriateness of these regimens in the indolent setting, largely due to their toxicity...Ferreri, A.J.M., et al. The Lancet Haematology 3, e217-e227 (2016).
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P
|
Rituxan (rituximab) • ibrutinib • cytarabine • dexamethasone • thiotepa
11ms
In cell lines and primary samples from chronic lymphocytic leukemia (CLL) patients, CG-806 suppressed BCR signaling (LYN, SYK, BTK, AKT, ERK) and pathways operative in AML (FLT3, AKT, CSF1R, MAPK, PDGFRα, others), killed malignant B-cell cells insensitive to ibrutinib or venetoclax at low nM concentrations, and showed enhanced activity in combination with venetoclax. CG-806 demonstrated a favorable safety profile in patients treated to date with 150, 300, 450 or 600 mg BID over multiple cycles. Oral absorption in patients produced plasma concentrations known to be effective in murine leukemia models. Pharmacodynamic studies using patient whole blood and plasma documented inhibition of SYK, BTK and ERK in the BCR signaling pathway.
Clinical • P1 data • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • CSF1R (Colony stimulating factor 1 receptor) • SYK (Spleen tyrosine kinase)
|
FLT3 mutation
|
Venclexta (venetoclax) • ibrutinib • luxeptinib (CG-806)
11ms
The integration of MFC results on BM samples with MYD88 mutation status assessed with a highly sensitive method such as dd-PCR may be considered as an alternative, less invasive method for the diagnosis of WM. Further analyses within this trial will assess the role of MFC combined with molecular profile of patients for the differential diagnosis between WM and other mature B-cell lymphoproliferative disorders as well as for the discrimination between WM and IgM monoclonal gammopathy of undetermined significance.
Clinical • IO biomarker
|
CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD19 (CD19 Molecule) • CD38 (CD38 Molecule) • CD5 (CD5 Molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • NCAM1 (Neural cell adhesion molecule 1)
|
MYD88 L265P
11ms
Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström’s macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female.
Clinical • P3 data
|
SYK (Spleen tyrosine kinase)
|
Tavalisse (fostamatinib)
11ms
Cases that need further attention by human experts will be flagged but will not account for more than 30% of all cases. This data will be extended in a prospective blinded study (clinicaltrials.gov NCT4466059).
CD20 (Membrane Spanning 4-Domains A1) • CD8 (cluster of differentiation 8) • CD19 (CD19 Molecule) • CD38 (CD38 Molecule) • CD79B (CD79b Molecule) • IL2RA (Interleukin 2 receptor, alpha) • CD5 (CD5 Molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • NCAM1 (Neural cell adhesion molecule 1)
11ms
P3, N=184, Not yet recruiting, Christian Buske | Trial completion date: Jun 2030 --> Sep 2027 | Initiation date: Jun 2020 --> Jan 2021 | Trial primary completion date: Jun 2030 --> Sep 2027
Clinical • Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD19 (CD19 Molecule) • CD38 (CD38 Molecule) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II) • MME (Membrane metallo-endopeptidase)
|
CD20 positive • CD5 positive
|
ibrutinib • carfilzomib
11ms
P1/2, N=146, Recruiting, ArQule | Trial completion date: Jun 2022 --> Nov 2022 | Trial primary completion date: Dec 2021 --> Nov 2022
Clinical • Trial completion date • Trial primary completion date
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 translocation • BTK mutation • BTK C481
|
MK-1026
11ms
Maintenance rituximab was planned every 3 months for 2 years...Workup for polycythAemia vera (PV), including JAK-2 and bone marrow, was not suggestive of PV. We labelled it as a case of polycythaemia due to undetermined aetiology.
Journal
|
JAK2 (Janus kinase 2)
|
Rituxan (rituximab)
11ms
P1, N=24, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Mar 2021 --> Sep 2022 | Trial primary completion date: Sep 2020 --> Sep 2022
Clinical • Trial completion date • Trial primary completion date
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive • CD20 expression
|
GDA-201
11ms
According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.
Review • Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
Venclexta (venetoclax) • Rituxan (rituximab) • ibrutinib • bortezomib • Ninlaro (ixazomib) • Calquence (acalabrutinib) • Brukinsa (zanubrutinib) • carfilzomib • bendamustine • Velexbru (tirabrutinib) • cyclophosphamide intravenous
11ms
By performing CRISPR/Cas9 KO studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in IL-10 production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL10 (Interleukin 10) • IL1B (Interleukin 1, beta)
|
MYD88 L265P
11ms
Clinical • Trial completion date • PD(L)-1 Biomarker
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • IGH (Immunoglobulin Heavy Locus) • CD5 (CD5 Molecule) • FCER2 (Fc Fragment Of IgE Receptor II)
|
Keytruda (pembrolizumab) • ibrutinib • Zydelig (idelalisib)
12ms
The bone marrow biopsy subsequently performed was normal. Radiation therapy led to a decrease in IgM level and normal κ/λ ratio with complete regression of the mass.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • TNFRSF8 (TNF Receptor Superfamily Member 8) • CD19 (CD19 Molecule) • PAX5 (Paired Box 5) • IRF4 (Interferon regulatory factor 4) • NCAM1 (Neural cell adhesion molecule 1) • SDC1 (Syndecan 1)
|
CXCR4 mutation • CD38 positive • SDC1 positive
12ms
Strikingly, RNF138 expression was positively correlated with NF-kB activation in lymphomas with MYD88L265P, but not in those without MYD88L265P. Collectively, our study reveals a novel mutation-specific biochemical reaction that drive B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT that is critical to innate immunity.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
MYD88 L265P • NFKB1 expression
12ms
Clinical • New P1 trial
|
CD20 (Membrane Spanning 4-Domains A1) • CD4 (CD4 Molecule)
|
Revlimid (lenalidomide) • Gazyva (obinutuzumab) • Onureg (azacitidine oral)
12ms
P1/2, N=14, Completed, Cancer Research UK | Recruiting --> Completed | N=81 --> 14 | Trial completion date: Jan 2022 --> Mar 2020 | Trial primary completion date: Jan 2022 --> Mar 2020
Clinical • Trial completion • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
|
Rituxan (rituximab) • BI-1206
1year
WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent...The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.
Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD38 (CD38 Molecule)
|
ibrutinib
1year
Clinical • Enrollment open • CAR T-Cell Therapy
|
CD19 (CD19 Molecule)
|
CD19 positive
|
fludarabine IV • cyclophosphamide intravenous
1year
Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
ibrutinib
1year
With the exception of pediatric lymphomas, neither PET/MRI (magnetic resonance imaging) nor whole-body MRI are currently endorsed by international guidelines, despite the fact that both techniques have clear advantages over &lsqb;18F]FDG-PET/CT in the assessment of lymphomas with variable FDG avidity. Of the new, more specific PET tracers that are being evaluated for the use in lymphomas, the CXCR4 (CXC motif chemokine receptor 4) tracer &lsqb;68Ga]Pentixafor is of particular interest, as initial studies have shown that it may be used to visualize frequently non-FDG-avid lymphomas such as small-cell lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma and lymphomplasmacytic lymphoma.
Review • Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
1year
The evidence for the use of Ibrutinib as a treatment option for relapsed/refractory WM is compelling in MYD88 mutated WM with the response and survival rates potentially better than conventional salvage chemoimmunotherapy. There is also a case for it to be used in the frontline setting in patients unfit for conventional frontline chemoimmunotherapy.
Review • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
Rituxan (rituximab) • ibrutinib
1year
Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).
Clinical • P2 data • Clinical Trial,Phase II • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
ibrutinib • Velexbru (tirabrutinib)
1year
Clinical • Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
ibrutinib
1year
Interestingly, WM cells express high levels of NAMPT (Nicotinamide phosphoribosyltransferase) compared to normal B cells and a combination of Ibrutinib and FK866 led to cell death independent of the mutational status of CXCR4. These data demonstrate that the naturally occurring antagonist CXCR4 EPI-X4 is able to impair growth and migration of WM cells by downregulating growth promoting kinases and NAMPT expression. These data shed light on a potentially crucial role of NAD metabolism for the growth on WM cells and pave the way to new innovative drugs by generating optimized EPI-X4 derivatives.
CXCR4 (Chemokine (C-X-C motif) receptor 4) • NAMPT (Nicotinamide Phosphoribosyltransferase)
|
ibrutinib • daporinad (APO866)
1year
Interestingly, WM cells express high levels of NAMPT (Nicotinamide phosphoribosyltransferase) compared to normal B cells and a combination of Ibrutinib and FK866 led to cell death independent of the mutational status of CXCR4. These data demonstrate that the naturally occurring antagonist CXCR4 EPI-X4 is able to impair growth and migration of WM cells by downregulating growth promoting kinases and NAMPT expression. These data shed light on a potentially crucial role of NAD metabolism for the growth on WM cells and pave the way to new innovative drugs by generating optimized EPI-X4 derivatives.
CXCR4 (Chemokine (C-X-C motif) receptor 4) • NAMPT (Nicotinamide Phosphoribosyltransferase)
|
ibrutinib • daporinad (APO866)
1year
Interestingly, WM cells express high levels of NAMPT (Nicotinamide phosphoribosyltransferase) compared to normal B cells and a combination of Ibrutinib and FK866 led to cell death independent of the mutational status of CXCR4. These data demonstrate that the naturally occurring antagonist CXCR4 EPI-X4 is able to impair growth and migration of WM cells by downregulating growth promoting kinases and NAMPT expression. These data shed light on a potentially crucial role of NAD metabolism for the growth on WM cells and pave the way to new innovative drugs by generating optimized EPI-X4 derivatives.
CXCR4 (Chemokine (C-X-C motif) receptor 4) • NAMPT (Nicotinamide Phosphoribosyltransferase)
|
ibrutinib • daporinad (APO866)
1year
In conclusion, bone marrow core biopsy evaluation is critical in the identification of unequivocal bone marrow infiltration by LPL/WM. In addition to MYD88p.L265P, somatic mutations in CXCR4, KMT2D, PRDM1/Blimp1, MYC and ID3 can appear in a fraction of LPL/WM.
Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4) • KMT2D (Lysine Methyltransferase 2D)
|
MYD88 L265P
1year
We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2 experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT (Signal Transducers and Activators of Transcription) signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage-mediated immune responses.
Journal
|
JAK2 (Janus kinase 2)
|
ibrutinib • Jakafi oral (ruxolitinib)
1year
IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.
Clinical • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P
|
Rituxan (rituximab) • Ninlaro (ixazomib) • dexamethasone
1year
Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton's tyrosine kinase inhibitor-based therapy...Ibrutinib is a suitable treatment option for both treatment-naïve and relapsing WM patients. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies. Current clinical trials are promising and may further advance WM-directed therapy.
Review • Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P
|
Rituxan (rituximab) • ibrutinib • bendamustine
1year
Serum β2-microglobulin could be a single biomarker strongly predictive of poor survival of WM patients, and the low-risk group of the IPSS-WM risk model including serum β2-microglobulin has better prognostic value than other risk models. Mutation analysis also might provide additional information to predict high-risk patients.
Clinical • Journal • Real-World Evidence
|
TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • B2M (Beta-2-microglobulin)
|
TP53 mutation • ARID1A mutation
|
Rituxan (rituximab)
1year
These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.
Review • Journal
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
1year
P2, N=50, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting
Clinical • Enrollment open
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
CXCR4 mutation • MYD88 mutation
|
Venclexta (venetoclax) • ibrutinib
over1year
P1, N=26, Recruiting, University of Michigan Rogel Cancer Center | Suspended --> Recruiting
Clinical • Enrollment open
|
JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • JAK3 (Janus Kinase 3) • TYK2 (Tyrosine Kinase 2) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1)
|
JAK3 mutation
|
Enpaxiq (pacritinib)
over1year
Clinical • Enrollment change
|
FLT3 (Fms-related tyrosine kinase 3)
|
Chr del(5q)
|
fludarabine IV • thiotepa • cyclophosphamide intravenous • mycophenolate mofetil • mycophenolate sodium • tacrolimus XR • tacrolimus intravenous
over1year
P1, N=30, Not yet recruiting, Bio-Path Holdings, Inc. | Initiation date: Feb 2020 --> Jun 2020
Clinical • Trial initiation date • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 expression
|
liposomal Bcl2 (BP1002)
over1year
Conclusions In our cohort rash, cardiac arrythmia and diarrhoea were the most clinically significant side effects. It is important to manage these side effects appropriately and use dose modifications to allow patients to gain maximum disease control with Ibrutinib.
Clinical • Real-World Evidence
|
TP53 (Tumor protein P53)
|
ibrutinib
over1year
The patient received six courses of rituximab, cladribine and dexamethasone, and a repeat bone marrow assessment showed reduction in the both clones but both were still detectable (LPL ˜7% and HCL ˜2%) respectively...The incidence of this Lymphoid+Lymphoid group of SDHMs is extremely low (0·66% in a study by Rouslan Kotchetkov et al, 2018). Co‐existent LPL and HCL have not been reported in the literature so far to the best of our knowledge.
BRAF (B-raf proto-oncogene) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL2RA (Interleukin 2 receptor, alpha) • CD123 (Interleukin 3 Receptor Subunit Alpha)
|
BRAF V600E • BRAF V600
|
Rituxan (rituximab) • cladribine • dexamethasone • Decadron (dexamethasone)
over1year
Rituximab, Cyclophosphamide, Dexamethasone (RCD) was the most common first‐line treatment (n = 18)...Alternative frontline regimens included R‐CVP (n = 4), R‐CHOP (n = 1) and R‐Bendamustine (n = 1)...Two patients had Bing‐Neel Syndrome and the third was frail and relapsed following first line Rituximab and Chlorambucil...Indeed, some unfit patients declined chemoimmunotherapy or were offered symptomatic management only. It is clear that many of these patients may have benefited from Ibrutinib and there will no doubt be an increase in Ibrutinib use going forward in this patient group.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
Rituxan (rituximab) • ibrutinib • dexamethasone • bendamustine • Leukeran (chlorambucil) • Decadron (dexamethasone) • cyclophosphamide intravenous
over1year
P1, N=26, Suspended, University of Michigan Rogel Cancer Center | Recruiting --> Suspended
Clinical • Trial suspension
|
JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • JAK3 (Janus Kinase 3) • TYK2 (Tyrosine Kinase 2) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1)
|
JAK3 mutation
|
Enpaxiq (pacritinib)
over1year
P2, N=50, Not yet recruiting, Dana-Farber Cancer Institute
Clinical • New P2 trial
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
|
CXCR4 mutation • MYD88 mutation
|
Venclexta (venetoclax) • ibrutinib
over1year
P2, N=33, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Sep 2021 --> Nov 2019
Clinical • Trial completion • Trial completion date
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 L265P • CXCR4 mutation
|
Rituxan (rituximab) • Ninlaro (ixazomib) • Decadron (dexamethasone) • Maxidex (dexamethasone eye drops, suspension)
over1year
P2, N=13, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=30 --> 13 | Trial completion date: Jan 2025 --> Jan 2022
Clinical • Enrollment closed • Enrollment change • Trial completion date
|
EGFR (Epidermal growth factor receptor)
|
Darzalex IV (daratumumab)
over1year
P1, N=30, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2019 --> Oct 2020 | Trial primary completion date: Oct 2019 --> Oct 2020
Clinical • Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor) • CD19 (CD19 Molecule) • CD34 (CD34 molecule)
|
peripheral blood stem cell transplantation
over1year
P2, N=40, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Jan 2025
Trial completion date • Trial primary completion date
|
NPM1 (Nucleophosmin 1) • IKZF1 (IKAROS Family Zinc Finger 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
|
NPM1 mutation • MLL rearrangement • CEBPA mutation • MLL rearrangement
|
mycophenolate mofetil
almost3years
Clinical • Enrollment open
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
|
Gazyva (obinutuzumab) • Obizur (susoctocog alfa)
3years
Clinical • New P2 trial
|
CD20 (Membrane Spanning 4-Domains A1)
|
CD20 positive
|
Gazyva (obinutuzumab) • Obizur (susoctocog alfa)