AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis

Key PointsAL patients with an initial dFLC <50 mg/L represent a distinct clinical subgroup with mostly renal disease and a favorable prognosis. These patients are evaluable for hematologic response including a novel low-dFLC partial response, which predict renal and overall survival.

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Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome

Blood ◽

10.1182/blood-2017-02-767467 ◽

2017 ◽

Vol 130 (5) ◽

pp. 625-631 ◽

Cited By ~ 51

Author(s):

Paolo Milani ◽

Marco Basset ◽

Francesca Russo ◽

Andrea Foli ◽

Giampaolo Merlini ◽

...

Keyword(s):

Clinical Features ◽

Light Chain ◽

Free Light Chain ◽

Al Amyloidosis ◽

Renal Survival ◽

Light Chain Amyloidosis ◽

Hematologic Response ◽

Heart Involvement ◽

Key Points

Key PointsPatients with AL amyloidosis and low dFLC burden (<50 mg/L) have less severe heart involvement and better survival. These patients are evaluable for hematologic response with adapted criteria predicting improvement of overall and renal survival.

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Bortezomib-Containing Regimens in the Treatment of AL Amyloidosis: A Single Center Experience

Blood ◽

10.1182/blood.v118.21.4614.4614 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4614-4614

Author(s):

Alessandro Re ◽

Gina Gregorini ◽

Annalisa Peli ◽

Matilde Nardi ◽

Claudia Crippa ◽

...

Keyword(s):

Light Chain ◽

Free Light Chain ◽

Cardiac Response ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Major Advance ◽

Single Center ◽

Hematologic Response ◽

Single Center Experience ◽

Grade 3

Abstract Abstract 4614 Treatment of patients (pts) with systemic AL Amyloidosis remains challenging and organ dysfunctions improve in not more than 1/3 of cases with standard treatment. Bortezomib has been reported to have activity in this disease, where the misfolded protein may render the amyloidogenic plasma cells particularly vulnerable to proteasome inhibition. To evaluate the feasibility and efficacy of Bortezomib, we report our single center experience with Bortezomib-containing regimens in pts with AL Amyloidosis. Hematologic responses and functional organ responses were evaluated according to the 2005 International Society of Amyloidosis criteria (Gertz et al, Am J Hematol 2005). Complete hematologic response (CR) was defined as normalization of the free light chain ratio with no evidence of a monoclonal protein by immunofixation and partial response (PR) as a 50% reduction in M-spike or absolute light chain level; moreover, dFLC (difference between involved and uninvolved free light chain) < 40 mg/L defined a very good PR (VGPR). A cardiac response was also defined by NT-proBNP criteria (>30% and >300 mg/L decrease in pts with baseline NT-proBNP > 650 mg/L). Since May 2010, 21 consecutive pts with AL Amyloidosis were treated with Bortezomib-containing regimens at our center: Bortezomib-Dexamethasone (Vel-D), 5 pts; Cyclophosphamide-Bortezomib-Dexamethasone (CyBOR-D), 14 pts; Bortezomib-Melphalan-Prednisone (VMP),2 pts. Median age was 62 years (43-74). Fifteen pts were treated upfront, while 7 had refractory or relapsed disease after several lines of therapy. According to the cardiac staging system based on NT-proBNP and troponin I, 6 (29%) pts were stage 1, 9 (42%) stage 2 and 6 (29%) stage 3. At the time of this report 9 pts, still on treatment, have received less than 4 cycles and are not yet evaluable for response. Twelve pts received a median of 5,5 cycles (range, 4–8) and were analysed for outcome. Five received Vel-D, 5 CyBOR-D and 2 VMP. Eight were treated upfront and 4 after previous treatment (including ASCT in 3). Ten (83%) had renal, 6 (50%) cardiac, 2 (17%) soft tissue, 3 (25%) nerve, 2 (17%) gastrointestinal tract and 1 (8%) liver involvement. Four pts (33%) achieved hematologic CR, 3 (25%) VGPR and 3 (25%) PR (overall hematologic response rate (ORR) 83%), with no difference in ORR between Vel-D and CyBOR-D. One pt had a stable disease and 1, treated for second relapse, had progressive disease and died. Median time to response was 2 months (2-4). One pt underwent HD-MEL after PR with Vel-D and 3 pts had peripheral blood stem cells collected (soon after diagnosis (2) and after initial response (1)) and cryopreserved (to perform ASCT if unsatisfactory response or relapse). Four of eight evaluable pts (50%) had a renal response and 4/6 (66%) had a cardiac response. Hematologic toxicity was negligible; 6 pts had significant extra-hematologic complications, including 3 heart failure, 2 interstitial and 1 bacterial pneumonia, 1 Staph. sepsis, 1 H1N1 virus infection, 1 CMV reactivation, 1 grade 3 neuropathy and 1 grade 3 diarrhoea. No pts died because of toxicity. CyBor-D was apparently better tolerated. In this unselected series of systemic AL Amyloidosis, Bortezomib-containing regimens produced rapid hematologic response in the great majority of pts, with and an high rate of organ response. Bortezomib represents a major advance in the clinical management of this disease. Disclosures: No relevant conflicts of interest to declare.

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Heavy/Light Chain Quantification Identifies Clonal Plasma Cell Disease in Patients with AL Amyloidosis and Normal Serum Free Light Chain Ratio

Blood ◽

10.1182/blood.v126.23.2956.2956 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2956-2956

Author(s):

Tatiana Prokaeva ◽

Brian Spencer ◽

Fangui Sun ◽

Nathaniel McConnell ◽

Richard M O'hara ◽

...

Keyword(s):

Overall Survival ◽

Binding Site ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

Al Amyloidosis ◽

Cell Disease ◽

Serum Free ◽

Serum Free Light Chain ◽

Combined Use

Abstract Background: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are routinely used for detection of clonal immunoglobulins (Ig) in AL amyloidosis. Serum free light chain (FLC) assays (Freelite®, The Binding Site Ltd., Birmingham, UK) have significantly improved the management of patients with AL amyloidosis by providing quantitative measure for the detection and monitoring of clonal plasma cell disease. However, up to 20% of patients with AL amyloidosis may have uninformative serum free light chain values. Objective: To assess the quantitative potential of serum Heavy/Light Chain (HLC) pairs (Hevylite®, The Binding Site Ltd., Birmingham, UK) assay in identification of clonal plasma cell disease in AL amyloidosis. Methods: One hundred and ninety-nine untreated patients with AL amyloidosis were included in this study. Patients with multiple myeloma or B cell lymphoproliferative diseases associated AL amyloidosis were excluded. Serum sampleswere obtained at initial evaluation and stored at -20°C. SIFE/UIFE were performed at the time of sample collection. HLC pairs were assessed by the Hevylite® assay. HLC κ/λ normal ratios (HLCR) were: 1.12-3.21 for IgG κ/λ; 0.78-1.94 for IgA κ/λ; and 1.18-2.74 for IgM κ/λ. FLCs were assessed by the Freelite® assay; FLC κ/λ normal ratio (FLCR) was 0.26-1.65. In 103 cases, FLC testing was performed at the time of sample collection; 96 cases were tested at The Binding Site. Vital status of patients was obtained from either medical records or Social Security Death Index. Follow-up ended in June 2014. Results: An abnormal HLCR was found in 74 (37.2%), an abnormal FLCR in 163 (81.9%), and SIFE/UIFE positivity in 187 (94%) of 199 patients with AL amyloidosis. Of 36 patients with a normal FLCR, 23 (63.9%) were noted with an abnormal HLCR compared to 51 (31.3%) patients in an abnormal FLCR group (P = 0.001). In total 186/199 (93.5%) patients with AL amyloidosis had abnormalities in either HLCR or FLCR, compared to 187/199 (94%) of patients who were SIFE/UIFE+ (Table 1). The combined use of both FLCR and HLCR yielded quantifiable information in 93.5% of cases; the use of both tests in combination with SIFE/UIFE identified plasma cell clonality in 100% of patients. Seventy-two cases presented with an abnormal HLCR for a single isotype and 2 in multiple Ig isotypes. In all cases, involved LC type of abnormal HLCR matched LC type identified by SIFE/UIFE. None of 12 cases that were negative on the SIFE/UIFE presented with an abnormal HLCR, however, all showed abnormalities in FLCR. Table 1. Comparative efficiency of FLCR, HLCR and Serum/Urine Immunofixation in AL Amyloidosis patients. SIFE/UIFE+ (n=187) SIFE/UIFE- (n=12) HLCR+/FLCR+ 51 (27.2%) - HLCR+/FLCR- 23 (12.3%) - HLCR-/FLCR+ 100 (53.5%) 12 (100%) HLCR-/FLCR- 13 (7%) - Overall survival was similar in patients with and without abnormal HLCR (Log rank p=0.092; Figure 1), whereas patients with an abnormal FLCR had a significantly inferior overall survival compared to those with a normal FLCR (Log rank p=0.027; Figure 2). Combined use of both HLCR and FLCR demonstrated a trend toward superior overall survival in a group of patients with an abnormal HLCR / normal FLCR (Wilcoxon p=0.037; Log rank p=0.107; Figure 3). Conclusions: The Hevylite® assay provided information in addition to other laboratory tests for clonal plasma cell disease in AL amyloidosis. The combined use of the HLCR and FLCR provided quantifiable information in 93.5% of patients. The use of both assays in combination with SIFE/UIFE detected clonal disease in all patients. HLCR has potential to quantify clonal disease in patients with uninformative FLCR results. An abnormal HLCR was not predictive of overall survival, while an abnormal FLCR was, in this series of patients. Combined use of HLCR and FLCR could be beneficial in prognostication of outcome in AL amyloidosis. Disclosures McConnell: The Binding SIte: Employment. O'hara:The Binding Site: Employment.

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Standard Oral Melphalan Chemotherapy for AL Amyloidosis Revisited Using the Serum Free Light Chain Assay.

Blood ◽

10.1182/blood.v106.11.3495.3495 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3495-3495 ◽

Cited By ~ 2

Author(s):

Mark Offer ◽

Ashutosh D. Wechalekar ◽

Hugh J.B. Goodman ◽

Julian D. Gillmore ◽

Helen J. Lachmann ◽

...

Keyword(s):

Partial Response ◽

Light Chain ◽

Nyha Class ◽

Single Agent ◽

Complete Response ◽

Free Light Chain ◽

Al Amyloidosis ◽

Serum Free ◽

Haematological Response ◽

Serum Free Light Chain

Abstract Treatment of systemic AL amyloidosis (AL) remains difficult, especially in older and sicker patients in whom dose intensive therapies are often associated with unacceptable morbidity and mortality. Many such patients continue to be treated with oral melphalan ± prednisone (MP) despite early trials having shown only very modest clinical efficacy, presumably encouraged by its perceived low toxicity. The recent advent of the sensitive nephelometric serum free light chain (sFLC) assay has for the first time enabled the typically subtle underlying clonal disease to be monitored in an effective quantitative manner in the majority of patients with AL. We report here sFLC responses and clinical outcome of patients with AL who received MP first-line and underwent serial evaluations at the UK National Amyloidosis Centre. The 90 patients comprised 46 males and 44 females with a median age of 68yrs (range 43–83). Median number of organs involved was 3 (1–4), including kidneys in 72%, heart in 56%, and liver in 29%. 16 (17%) had ≥ NYHA class III heart failure. Median ECOG performance status was 1. Median follow-up was 2.3 yrs (0.3–14). 60 patients received oral melphalan with prednisone, and 30 received single agent melphalan. Patients received a median of 6 cycles of treatment (range 1– 26), and the sFLC assay was scheduled following each cycle after availability of the assay and retrospectively on stored sera for earlier patients. Haematological response data using sFLC assay were evaluable in 54 (60%). Responses were defined as complete response (CR) - sustained normalisation of sFLC ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. There was a haematological response in 22 (40%) of evaluable patients. 4 (7%) had a complete response, 18 (33%) had a partial response and 32 (59%) did not respond. 42% of patients treated with single agent melphalan responded compared with 39% of those treated with melphalan and prednisone (p=0.8). Responders received a median 6 cycles of treatment, and complete responders received a median of 14 cycles. Non-responders received a median of 5 cycles of treatment. The median time to commencing further chemotherapy was 5 months. The median overall survival (OS) was 5.8yrs, but most patients received further salvage treatments and the influence of MP treatment on OS could not be ascertained. Toxicities during MP were seen in 13 (14%) cases, including myelodysplasia in 2 patients. There were no treatment related deaths. In conclusion, use of the sFLC assay confirms that response of the underlying clonal plasma cell disease to standard oral melphalan and prednisone is poor in AL amyloidosis, and that response is usually very delayed even among patients who respond completely. Encouragingly however, toxicity was low among this relatively old and sick cohort of patients. These findings support frequent sFLC measurements in AL patients receiving MP to enable rational treatment decisions to be made at the earliest opportunity.

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Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

Journal of Clinical Oncology ◽

10.1200/jco.20.01285 ◽

2020 ◽

Vol 38 (28) ◽

pp. 3252-3260 ◽

Cited By ~ 3

Author(s):

Efstathios Kastritis ◽

Xavier Leleu ◽

Bertrand Arnulf ◽

Elena Zamagni ◽

María Teresa Cibeira ◽

...

Keyword(s):

Overall Survival ◽

Light Chain ◽

Response Rate ◽

Alkylating Agents ◽

Standard Of Care ◽

Phase Iii ◽

Controlled Study ◽

Al Amyloidosis ◽

Open Label ◽

Hematologic Response

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

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Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial

Blood ◽

10.1182/blood-2012-01-407791 ◽

2012 ◽

Vol 119 (21) ◽

pp. 4860-4867 ◽

Cited By ~ 80

Author(s):

Shaji K. Kumar ◽

Suzanne R. Hayman ◽

Francis K. Buadi ◽

Vivek Roy ◽

Martha Q. Lacy ◽

...

Keyword(s):

Partial Response ◽

Light Chain ◽

Gastrointestinal Symptoms ◽

Long Term Results ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Phase 2 ◽

Hematologic Response ◽

Phase 2 Trial ◽

Grade 3

Abstract Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).

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Serum Free Light Chain Responses after High-Dose Intravenous Melphalan and Autologous Stem Cell Transplantation for AL (Primary) Amyloidosis.

Blood ◽

10.1182/blood.v104.11.942.942 ◽

2004 ◽

Vol 104 (11) ◽

pp. 942-942

Author(s):

Vaishali Sanchorawala ◽

Daniel G. Wright ◽

Barbarajean Magnani ◽

Martha Skinner ◽

David C. Seldin

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Serum Free ◽

Hematologic Response ◽

Serum Free Light Chain

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses of plasma cell dyscrasias underlying AL amyloidosis following HDM/SCT and other forms of treatment. The definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic response as a ≥ 50% reduction in free light chain (FLC) measurements. Hematologic responses by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a retrospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which hematologic CR, by our standard criteria, correlates with FLC response. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 67 patients with AL amyloidosis before and after treatment with HDM/SCT. After treatment with HDM/SCT, 27 patients (40%) achieved a CR by standard criteria. Of these 27 patients, 63% (n=17) demonstrated normalization of FLC levels and an improvement of ≥50% in FLC occurred in 100%. Of the 40 patients who did not achieve a CR, 25% (n=10) experienced normalization of FLC levels, and an improvement of ≥50% occurred in 78% (n=31), while only 5 patients (13%) experienced no significant change in FLC. The average improvement in FLC was 94% for patients who achieved a CR by standard criteria and 72% for those who did not (p=0.0001, t-test). Thus, HDM/SCT was found to induce improvements in FLC levels of ≥50% in the vast majority of AL amyloidosis patients treated with HDM/SCT (87%, or 58/67). These data indicate that a decrease in FLC of ≥50% is a substantially less stringent indicator of hematologic response than is CR, as defined by standard criteria. Nonetheless, these measures of hematologic response are complementary, since decreases in FLC can be detected earlier following treatment than changes in IFE and marrow studies required to determine CR.

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Overview of the French Practice: Therapeutic Strategies in Patient's First Relapse or Refractory Non IgM AL Amyloidosis

Blood ◽

10.1182/blood-2018-99-114834 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3297-3297 ◽

Cited By ~ 1

Author(s):

Camille Villesuzanne ◽

Stephanie Harel ◽

Alexis Talbot ◽

Bruno Royer ◽

Naelle Lombion ◽

...

Keyword(s):

Overall Survival ◽

Partial Response ◽

Al Amyloidosis ◽

Line Treatment ◽

First Line ◽

Hematologic Response ◽

Organ Response ◽

Grade 3 ◽

First Line Treatment

Abstract First line treatment of systemic non IgM AL amyloidosis is well defined in the recommendations of the French National Reference Center for AL amyloidosis. Melphalan or cyclophosphamide at standard dose with dexamethasone in combination with bortezomib are currently recommended. The objective is to rapidly obtain an hematological response, modulating treatment according to severity of heart involvement and hematologic response. At relapse there are no such precise guidelines. If the initial treatment has been effective, it may be chosen in case of late relapse occurring after at least one year. Combination of other drugs effective in plasma cell dyscrasias might be proposed, but studies on treatment in the relapse setting are scarce and a consensus remains to be established. Here we report a multicenter retrospective study assessing treatment at relapse and evaluating their impact on hematologic response, progression-free survival (PFS), overall survival, organ responses and toxicity. We included 84 patients who received, from 2006 to 2014, as first line treatment, a non-intensive chemotherapy in 15 French hospital centers. At diagnosis, 47 (56 %), 51 (61%) and 16 (19%) patients respectively presented with heart, kidney, and neurological involvement. Twenty three patients (27%) had a severe heart disease with a Mayo Clinic stage III. The median follow-up of the cohort was 58 months (9-135). The hematological response was assessed at 3 months based on free light chain measurement, according to the international consensus. At relapse, 29 patients (34,5%) received a bortezomib, cyclophosphamide and dexamethasone combination (VCD) resulting in 79% of very good partial response (VGPR) or better and 7% of partial response (PR), 18 patients (21%) had an organ response, and with a median follow up of 70,5 months (9,03-135) the estimated overall survival at 3 years was 79,4%. Twenty six patients (31%) experienced grade ≥ 3 toxicities that were peripheral neuropathy in 5 patients. Seventeen patients (21%) received a combination of lenalidomide and dexamethasone (RD), resulting in 17% of VGPR or better and 35% of PR, 12 % of organ response with an estimated overall survival at 3 years of 94% with a median follow up of 46,5 months (20,99-122,97). Four patients (23%) had a grade ≥ 3 toxicity, mainly hematologic. Five patients (6%) received a combination of bortezomib with lenalidomide and dexamethasone (VRD) resulting in VGPR or better in 4 patients and PR in 1 patients, 4 patients had an organ response with all patients being alive at 3 years. Grade ≥ 3 toxicity was observed in 1 patient. Regarding these 3 combinations, the median PFS were respectively 22 months for VCD, 8 months for RD (p = 0, 0012) and 17.3 months for VRD. At relapse 13 other therapeutic combinations were used. Other IMIDs (thalidomide or pomalidomide), melphalan, bendamustine or daratumumab were given to 4, 8, 6 and 5 patients respectively resulting in 1, 4, 3 and 1 of VGPR or better hematologic response. Bendamustine containing regimens were associated in grade ≥ 3 toxicity in 5 patients (83%). Sixty-seven patients (79%) were still alive at 3 years. In conclusion, there is currently no consensus on the best treatment for AL amyloidosis patients in relapse. This study shows the different regimens used in France and their effectiveness in relapse. As usual in this disease the survival of relapsing patients is good with almost 80% of patients alive at 3 years. Bortezomib remains an important molecule in relapse. Lenalidomide alone with dexamethasone seems to be less effective to obtain a high rate of hematologic response. VRD has been used in few patients, we found no cumulative toxicity with the combination of proteasome inhibitor and lenalidomide with a very interesting response rate, PFS, OS and organ responses. VRD should be tested more systematically in relapsing or refractory patients. Finally, the role of daratumumab and new proteasome inhibitors remains to be defined. Disclosures Harel: janssen: Consultancy; takeda: Consultancy; amgen: Consultancy.

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