Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON) : a multicentre, open-label, single-arm, phase 2 trial

Background Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m(2)) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-totreat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials. gov, number NCT02460276. Findings Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17.8 months (IQR 14.7-20.9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.Peer reviewe

Hepatocyte growth factor, c-Met and syndecan-1 in multiple myeloma

HEPATOCYTT-VEKSTFAKTOR, C-MET OG SYNDECAN-1 I MYELOMATOSE Myelomgruppen ved IKM forsker på sykdommen myelomatose, en form for benmargskreft. Gruppens arbeid har vært fokusert på hvordan miljøet i benmargen, med løselige og cellebundne vekstfaktorer, påvirker kreftcellene/myelomcellene. En av flere vekstfaktor i benmargen er hepatocyttvekstfaktor (HGF). Myelomgruppen var de første til å vise at myelomceller produserer HGF og samtidig uttrykker dens receptor c- Met. Gruppen og andre har vist at høye nivåer av HGF i serum er et dårlig prognostisk tegn hos myelomatosepasienter, at HGF stimulerer vekst og overlevelse av myelomceller, og kan være viktig for den ødeleggelse av bein som sees ved myelomatose. Dette doktorgradsarbeidet fokuserer på HGF og c-Met og på syndecan-1, som er en viktig regulator av aktiviteten av vekstfaktorer i benmargen. I tillegg har vi undersøkt forekomsten av avvik i kromsomene i kreftcellene hos pasienter med myelomatose. I den første artikkelen ønsket vi å undersøke hvorvidt HGF og c-Met er tilstede, og om systemet er aktivt, også i vev fra pasienter, og ikke bare i cellelinjer på laboratoriet. Vi undersøkte forekomsten av HGF og c-Met i benmargsprøver fra pasienter med myelomatose og beslektede sykdommer ved hjelp av immunfarging. 58 av 68 biopsier fra myelomatosepasienter, og 9 av 10 biopsier fra normal benmarg var positive for HGF. 25 av 63 biopsier fra myelomatosepasienter og ingen av 10 biopsier fra normal benmarg var positive for c-Met. Med fosfo-spesifikke antistoffer fant vi at c-Met var fosforylert (dvs aktivert) i 15 av 21 c-Met-positive pasienter. Dette viser at c-Met ikke bare er tilstede, men at det også går et aktivt signal gjennom denne. Studien indikerer at c-Met er en faktor som skiller maligne fra normale plasmaceller, og at c-Met er aktivert i myelomatosepasienter. Omdanning av HGF fra inaktiv til aktiv form er avgjørende for biologisk funksjon. I den andre artikkelen undersøkte vi serumnivået av HGF aktivator (HGFA), som er en av de viktigste aktivatorer av HGF. Vi fant høyere serumnivåer av aktivert HGFA hos myelomatosepasienter enn hos friske kontrollpersoner. En mulig mekanisme for aktivering av HGF i myelomatose kan være økt nivå eller aktivitet av HGFA. En ekstracellulær porsjon av c-Met kan kappes av til en løselig reseptor i serum. Den løselige reseptoren kan nedregulere effekten av HGF på flere måter, men dette har ikke vært undersøkt i myelomatose. I den tredje artikkelen undersøkte vi serumnivåer av løselig c-Met. Vi fant ingen forskjell i serumkonsentrasjon av løselig c- Met mellom myelomatosepasienter og friske kontrollpersoner. Likevel var det en negativ korrelasjon mellom serumkonsentrasjon av c-Met og sykdomsstadium, grad av plasmacelleinfiltrasjon i benmarg og nivå av Mkomponent hos myelomatosepasienter. Studien indikerer at det kan være relevant å undersøke en mulig biologisk betydning av løselig c-Met i myelomatose. Syndecan-1 er en viktig regulator av aktiviteten av flere vekstfaktorer. I den fjerde artikkelen undersøkte vi rollen til syndecan-1 som cofaktor i interaksjonen mellom HGF og c-Met. Det er kjent fra før at HGF kan binde til syndecan-1. Vi viser i denne studien at også c-Met kan binde til syndecan-1. Det er også tidligere vist at syndecan-1 lokaliseres til lipid rafts – kolesterolrike ”fett-flåter” – i cellemembranen. Slike lipid-flåter er viktige i cellesignalering, fordi viktige signalmolekylær konsentreres hit. Vi fant at HGF og c-Met lokaliseres sammen med syndecan-1 til lipid-flåter i myelomceller, og at intakte lipid-flåter er nødvendige for HGF-indusert signalering via PI3K-Akt, som er en viktig signalvei for overlevelse og tilvekst av myelomceller. Det at myelomcellene er avhengig av faktorer i benmargen er én side av sykdomsutviklingen ved myelomatose. En annen side er genetiske forandringer i myelomcellene. I den femte artikkelen har vi undersøkt forekomsten av genetiske avvik i myelomcellene hos 250 norske myelomatosepasienter. Vi fant at 45% av pasientene hadde en translokasjon (overbytning av genmateriale) der immunglobulingenet, som er sentralt ved myelomatose, blir flyttet nært andre gen (onkogen) som ofte fremmer celleveksten. 35% hadde tap av deler (delesjon) av kromosom 13 og 19% hadde delesjon av kromosom 17. 10% hadde delesjon av korte armen av kromosom 1 og 34% hadde amplifikasjon av den lange armen av kromosom 1. Forekomsten av de genetiske avvikene hos norske myelomatosepasienter er lik den som er beskrevet i internasjonale materialer. Genetiske avvik kan komme til å få betydning for hvilken behandling som skal gis. Metoder som er brukt i doktorgradsarbeidet er immunhistokjemi, ELISA, konfokalmikroskopi, flowcytometri, immunprecipitering, Western blot og interphase FISH

Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B

Background: Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. Results: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. Conclusions: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling

BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis

In this study, we analyzed the prevalence and clone size of BRAF V600E mutation in 209 patients with multiple myeloma and related the results to clinical phenotype, response and survival. Biopsies were screened for BRAF V600E by allele-specific real-time PCR (AS-PCR). Positive results were confirmed by immunohistochemistry, Sanger sequencing and, in three patients from whom we had stored purified myeloma cells, whole-exome sequencing. Eleven patients (5.3%) were BRAF V600E mutation positive by AS-PCR and at least one other method. The fraction of mutated cells varied from 4 to 100%. BRAF V600E-positive patients had no characteristic clinical phenotype except for significantly higher levels of serum creatinine (125 versus 86 μmol/l) Seven of eleven patients responded with at least very good partial response to alkylators, immunomodulatory agents or proteasome inhibitors. Progression-free and overall survival were similar in patients with and without the mutation. By this integrated approach, we found that patients with BRAF V600E mutation responded very well to broad acting drugs and there was no relation to prognosis in early-stage myeloma. In particular, a large mutated cell fraction did not correlate with aggressive disease

MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma: the Nordic Lymphoma Group MCL7 VALERIA trial

Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multicenter phase 1b/2 trial, we evaluated safety and efficacy of minimal residual disease (MRD)-driven venetoclax, lenalidomide, and rituximab (venetoclax-R2) in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary end point was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; if MRD-negativity was then confirmed, treatment was stopped. In total, 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a Bruton tyrosine kinase (BTK) inhibitor. Median progression-free survival (PFS) was 21 months, with median overall survival of 31 months. TP53 mutation was associated with inferior PFS (P &lt; .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remain MRD negative after a median of 17.4 months. Hematological toxicity was frequent, with 52 of 59 (88%) patients with G3-4 neutropenia and 21 of 59 (36%) patients with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax-R2 is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure. This trial was registered at www.ClinicalTrials.gov as #NCT03505944.</p

Economic Illusions Underlying Law

Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma.This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON) : A multicentre, open-label, single-arm, phase 2 trial

Background: Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m2) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-to-treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. Findings: Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7-20·9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation: Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial. Funding: Janssen and Celgene

Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population-based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow-up of patients still alive at analysis was 40 months for the high-dose (HDT)-treated ones and 29 months for the whole population. Three hundred forty-seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14; 16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3-yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P <0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3-yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3-yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P <0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted