Utilizing Clinical Features of Progression to Predict Richter's Syndrome in Patients with CLL Progressing after Ibrutinib

Abstract Background: Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib. Methods: We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model. Results: We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9). Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither. Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A). To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither. Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01). Conclusions: Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. Figure 1 Figure 1. Disclosures Kittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

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BTK and/or PLCG2 Mutations in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib: Characteristics and Outcomes at the Time of Progression

Blood ◽

10.1182/blood-2019-125411 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3050-3050 ◽

Cited By ~ 1

Author(s):

Paul J. Hampel ◽

Timothy G. Call ◽

Sara J. Achenbach ◽

Kari G Rabe ◽

Wei Ding ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Resistance Mutation ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Data Safety ◽

Safety Monitoring Board ◽

Progression Of Disease ◽

Richter’S Transformation ◽

Richter's Transformation

INTRODUCTION Mutations in BTK and PLCG2 have been reported to occur in ~80% of CLL patients (pts) who have progression of disease on ibrutinib therapy (Woyach, JCO 2017; Ahn, Blood 2017). These mutations are described as appearing months before actual relapse and thus considered as a potential predictive biomarker for future relapse (Quinquenel, Blood 2019). However, the outcomes of these pts after disease progression are not well described. In this study, we seek to investigate time to next therapy and overall survival (OS) following progression among CLL pts on ibrutinib therapy with and without these resistance mutations. METHODS Between 10/2012 and 6/2019, we identified 34 pts in the Mayo Clinic clinical CLL resource who progressed while receiving ibrutinib therapy and also had testing for BTK and PLCG2 mutation performed as part of routine clinical practice at either NeoGenomics Laboratories or The Ohio State University. OS was calculated from time of ibrutinib progression to last known alive or death date; OS was plotted using Kaplan Meier methods and was compared using the log-rank test between various groups (e.g., mutation positive vs negative; CLL progression vs Richter's). Cumulative incidence of time to next treatment in those who had a treatment after progression was adjusted for the competing risk of death. RESULTS Of 34 pts who progressed while receiving ibrutinib, 26 pts experienced CLL progression and 8 pts had Richter's transformation; baseline characteristics in Table 1A. The presence of a BTK or PLCG2 mutation was found in 20/34 (59%) pts (specific mutations in Table 1B). BTK mutation alone was present in 9 pts, 7 pts had PLCG2 mutation alone, and 4 pts had both mutations. Median time between a positive test and start of next therapy was 4 months (range 1-19 months) and did not vary between BTK vs PLCG2 mutations. Among the 26 pts with CLL progression, 18 (69%) pts had a mutation present: BTK alone (n=8), PLCG2 alone (n=6), both (n=4). Therapy following progression on ibrutinib in these pts was as follows: venetoclax (n=16; 11 pts who continued ibrutinib in combination), idelalisib (n=4), investigational treatments (n=2), continued ibrutinib alone (n=2), dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; n=1), and unknown (n=1). Twelve of the 26 pts with CLL progression on ibrutinib, including 8 pts with a prior resistance mutation detected, had subsequent progression of disease on the aforementioned next line therapy. Treatment of these patients consisted of the following: restarted ibrutinib in addition to current treatment of venetoclax (n=5), venetoclax (n=2), pembrolizumab (n=2; 1 pt with continued ibrutinib), obinutuzumab with continued ibrutinib (n=1), gemcitabine and vinorelbine with continued ibrutinib (n=1), and no further treatment (n=1). Among the 8 pts with Richter's transformation as the initial progression event on ibrutinib after mutation testing, 1 pt had a BTK mutation and 1 pt had a PLCG2 mutation. Treatments following progression on ibrutinib included multi-agent chemoimmunotherapy (n=3; 2 pts received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP] with continued ibrutinib and 1 pt received doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD] alone), pembrolizumab (n=3; 1 pt in combination with continued ibrutinib), venetoclax in combination with continued ibrutinib (n=1), and venetoclax and obinutuzumab (n=1). The median time to next treatment (second line of treatment beyond ibrutinib) for the 31 pts who started another therapy following progression on ibrutinib was 16.7 months (95% CI 9.6-NE; Figure 1A) and was not significantly different for pts with or without a resistance mutation (p=0.57). Median OS for all 26 pts with CLL progression was 28.7 month and there was no difference according to presence or absence of a resistance mutation (median 28.7 months vs 18.2 months, p=0.53; Figure 1B). The 8 pts with Richter's transformation had a median OS of 7.1 months (95% CI 2.0-NE). CONCLUSION Approximately 60% of pts tested in this progression cohort had a BTK or PLCG2 mutation at time of or preceding progression on ibrutinib therapy. OS and time to next therapy did not differ statistically between pts with mutated vs non-mutated clones; however, caution should be applied with the conclusions given the limited sample size. Disclosures Ding: DTRM Biopharma: Research Funding; Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:Ascentage Pharma: Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding.

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The Role of Serum Immunoglobulin Free Light Chain In Response and Progression In Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v116.21.3095.3095 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3095-3095

Author(s):

Xavier Leleu ◽

Wanling Xie ◽

Meghan Rourke ◽

Ranjit Banwait ◽

Renee Leduc ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Response Rate ◽

Early Response ◽

Response To Therapy ◽

Time To Progression ◽

Therapy Initiation ◽

M Spike

Abstract Abstract 3095 Introduction: Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by the secretion of IgM protein in the serum. The IgM level lacks sensitivity due to its prolonged half-life. The serum free light chain (sFLC) assay has shown significant clinical application in plasma cell dyscrasias, specifically in multiple myeloma, and is used to monitor response to therapy. In this study, we sought to examine the role of sFLC in the response and progression of patients with WM. Methods: This study was performed using serum collected from a homogeneous cohort of patients diagnosed with WM and uniformly treated on a phase 2 trial using the combination of bortezomib with rituximab, previously untreated (N=26) or relapsed and or refractory to prior therapy (N=37). Patients eligible for this analysis must have measurable sFLC levels at baseline. A total of 48 patients were included. FLC response is defined as achievement of normal iFLC value or 50% decrease from baseline in the iFLC level during therapy and follow-up. Concordance between FLC and IgM response rate was evaluated using Kappa statistics. Correlation was evaluated using Spearman correlation coefficient. Time to progression was estimated using Kaplan-Meier methodology. We also did landmark analysis to compare overall response rate and time to progression by FLC or IgM response status at 2 months after therapy initiation; Fisher Exact test or Log-rank test were used. Results: The median iFLC value was 103.50mg/L (range 22.5–3540), the median kappa over lambda ratio was 13.45 (0.01-665), and the median serum IgM value by nephlometry was 3995 mg/dL (537-10,800). Overall, as per M spike response criteria, 29 (60%, 90% CI: 48%, 72%) patients responded, e.g. had partial response or better, and 19 patients failed to obtain response. Using serum IgM protein measurement by nephlometry during therapy and follow up post-therapy, 35 (73%, 90% CI: 60%, 83%) patients responded with a PR or better (>50% decrease), with 3 (6%) having normalization of their serum IgM. In comparison, iFLC response during treatment and follow up occurred in 38 (79%, 90% CI: 67%, 88%): with 2(4%) having normalization of value, 21(44%) having 50% reduction and 15(31%) having both. The time to iFLC response and IgM response among patients who achieved response by both criteria was calculated (N=33). The median time to iFLC response was 2.1 months (range 0.9–28.7months), while the median time to IgM response was 3.0 months (0.9-14.7) (p=0.07). The median time to progression per the protocol was 18.9 months (95% CI:10.5-NR). The Kappa concordance between iFLC 25% increase and M spike progression was 0.63 (95% CI: 0.41–0.84). This showed a better concordance compared to using the iFLC >50% definition (kappa=0.58, 95% CI: 0.35, 0.81), indicating that progression using iFLC>25% would be a better definition for patients with WM. The median time to progression by iFLC>25% increase was 13.7 months (95% CI:10.9-19.4) and the median time to IgM >25% increase was 14.6 months (95% CI: 9.5–19.1), showing a more rapid detection of progression by iFLC compared to M spike and IgM measurements. We next examined whether attaining a response using iFLC can be a predictor of overall response to therapy. Seventeen patients (35%) achieved an iFLC response at 2 months after therapy initiation. Patients with early iFLC response were more likely to have intermediate/high ISS-WM stage, elevated B2M or low Hemoglobin<11.5 gm/dL (p<0.05). Early iFLC response was related to overall IgM response during therapy and follow up (p=0.02). In multivariable models when adjusting for ISS stage, B2M or Hgb, there was no significant association between FLC early response and TTP either by protocol, FLC or IgM criteria. However, there was trend that early response was related to prolonged TTP especially when adjusting for hgb risk factors (HRs ranges from 0.63∼0.80, p>0.3 for various TTP endpoints. Conclusion: iFLC may be a useful marker of tumor measurement that correlates well with IgM and M spike measurements. The time to iFLC response was shorter by 1 month compared to IgM or M spike measurement. The median time to progression by iFLC was shorter by 1 month compared to IgM. There was a trend that early response was related to prolonged TTP when adjusting for other risk factors. Disclosures: Leleu: Celgene: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria.

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Allogeneic Stem Cell Transplantation (allo-SCT) in 192 Acute Myeloid Leukemias (AML): A Single Center Experience From 1982 to 2010

Blood ◽

10.1182/blood.v118.21.4498.4498 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4498-4498

Author(s):

Carmen Montes-Gaisan ◽

Jorge Monge ◽

Clara Martin ◽

Zurie Diez ◽

Johny Alberto Hinostroza ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Multivariable Analysis ◽

The Other ◽

Univariable Analysis ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source

Abstract Abstract 4498 Background: Giving the fact that allo- SCT currently offers patients with high risk AML the best chance of cure, we`ve aimed to investigate the outcome of AML patients who have undergone allo-SCT in our center, considered as one of spanish reference hospital in SCT, and the parameters that have been able to influence in relapse rate (RR), overall survival (OS) and relapse free survival (RFS). Methods: Retrospective study in 192 AML patients who have undergone allo-SCT between 1982 and 2010. The analysis has been performed in 171 patients (85 male and 86 female) by excluding 21 acute promyelocitic leukemias (APL): 65 patients until 1999 and 106 since 2000. Median age was 37 1874 and median lecocyte count, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(13400/\hbox{ L }\frac{470}{250000}\) \end{document}. 82 were de novo AML and 87 were in morfologic complete remission (70 in first CR). 14 patients had received a previous SCT. Cytogenetic risk was as follows: 55 intermediate, 34 high and 11 low. Conditioning regimen was ablative in 162 patients: CyTBI (36), BuCy (31), BuFlu (30) and others (3). 130 patients (76) underwent a related allo-SCT (95 of them were matched) and 41 patients (24), an unrelated allo-SCT (64 of them were matched). Stem cell source was bone marrow (BM) in 146 patients (85) and only 3 patients received umbilical cord (UC). Graft versus host disease (GvHD) prophilaxis was based on Ciclosporine in 150 patients (88). Median time from last treatment was 73 days 12268. Results: The median follow-up of this study was 61 months 1317. OS at 1, 3 and 5 years were 57, 44 and 40. RFS at 1, 3 and 5 years were 62, 50 and 45. Early mortality (before day 100) was 26 (43 until 1999 and 15 since 2000, p0,0001): 18 patients because of infections, 10 because of toxicity, 9 because of disease and 7 because of EICH. Late mortality was 27 (more than the half because of relapse, with no significant difference between 19881999 and 20002010). Cumulative relapse incidence at 5 years was 35, with a median time of relapse of 4 months. Secondary malignancies incidence was 5. Multivariable analysis showed that Transplantation Related Mortality (TRM) was influenced by: year of allo-SCT (OS at 5 years of 49 if 20002010 vs 28 if 19821999, p0,0001), late engraftment (p0,002) and severe acute GvHD (OS at 5 years of 45 if no evidence/grade I-II vs 25 if grade III-IV, p0,071). The other important parameters which lost its univariable analysis significance were donor type, recipient age and conditioning regimen. No difference was found in case of HLA and ABO discordance or donor/recipient CMV status. Multivariable analysis also showed that RR and RFS at 5 years was influenced by: disease status at allo-SCT (50 if 1CR vs 0 if 2CR/PR/refractory disease, p0,002), chronic GvHD (67 if present vs 41 if absent, p0,035) and leucocyte count at diagnosis (54 if 20000/ L vs 37 if 20000/ L, p0,038). The other important parameters which lost its univariable analysis significance were cytogenetic risk, initial induction response and positive minimal residual disease (MRD) before allo-SCT. No diference was found in case of ethiologic classification or stem cell source. Conclusions: Allo-SCT is a curative procedure in AML patients (global RFS of 50 at 3 years), specially when disease is under control and patient develops chronic GvHD. In the last decade, there have been important improvements in the procedure which have led to a significant decrease in TRM, and consequently, a significant increase in OS. Disclosures: No relevant conflicts of interest to declare.

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Evaluation Of The Novel, Orally Bioavailable Selective Inhibitor Of Nuclear Export (SINE) Verdinexor (KPT-335) In Spontaneous Canine Cancer: Results Of Phase I and Phase II Clinical Trials

Blood ◽

10.1182/blood.v122.21.5149.5149 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5149-5149

Author(s):

Cheryl London ◽

Luis feo Bernabe ◽

Sandra Barnard ◽

William Kisseberth ◽

Antonella Borgatti ◽

...

Keyword(s):

Biological Activity ◽

Tumor Cell ◽

Median Time ◽

Cell Lines ◽

Nuclear Export ◽

Research Funding ◽

Tumor Cell Lines ◽

Time To Progression ◽

Orally Bioavailable

Abstract SINE (Selective Inhibitors of Nuclear Export) block the activity of XPO1/CRM1, 1 of 7 nuclear export proteins in cells, forcing the nuclear retention of key tumor suppressor proteins (TSP), leading to selective apoptosis of tumor cells. The purpose of these studies was to evaluate the in vitro activity of SINE against canine tumor cell lines and investigate the biological activity of Verdinexor (KPT-335) in dogs with spontaneous cancers as proof of principle for human clinical studies with SINE. Several different canine tumor cell lines including those derived from Non-Hodgkin Lymphoma (NHL) exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of Verdinexor was performed in dogs with cancer with an emphasis on NHL given in vitro activity demonstrated against the tumor cell lines. The maximum tolerated dose (MTD) was 1.75 mg/kg twice per week although biological activity was observed at 1 mg/kg. Clinical benefit including Partial Response (PR) and Stable Disease (SD) for at least 4 weeks was observed in 9/14 dogs with NHL with a median time to progression of 66 days (range 35-256). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg Verdinexor on a Monday/Wednesday/Friday (MWF) regimen; clinical benefit (PR + SD) was observed in 4/6 dogs with a median time to progression of 83 days (range 35-250+). Toxicities were primarily gastrointestinal in nature consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care and dose modulation. A validated health related Quality of Life (QOL) form used to assess dogs during treatment demonstrated that the overall quality of life did not decrease in dogs in this study supporting the notion that clinical toxicities associated with Verdinexor are generally well tolerated. Based on these findings, a Phase IIb study was performed in 58 dogs with either newly diagnosed or relapsed NHL. Drug was administered initially at 1.5 mg/kg MWF, but this dosing regimen was changed to 1.25 mg/kg M/Th due to the high rate of anorexia and weight loss on the MWF regimen; dose escalation was permitted to 1.5 mg/kg on the M/Th regimen. The objective response rate was 34% (1 CR, 19 PR) with an additional 33 dogs experiencing SD for a minimum of 4 weeks, resulting in a of 91% disease control rate. While the median time to progression was approximately 5 weeks, 19 dogs (32%) remained on study drug for >8 weeks; several dogs continue to receive Verdinexor. Laboratory abnormalities were minimal and clinical toxicities were mild on the M/Th regimen. Together, these data provide robust evidence that the novel orally bioavailable XPO1 inhibitor Verdinexor exhibits single agent biological activity in a spontaneous large animal model of human NHL. Furthermore, Verdinexor was well tolerated even in the absence of supportive care, suggesting that SINE compounds could exhibit good long-term tolerability in people. Disclosures: London: Zoetis: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Abbott: Honoraria. Modiano:Karyopharm: Research Funding. Saint-Martin:Karyopharm: Employment. McCauley:Karyopharm : Employment, Equity Ownership, Patents & Royalties. Shacham:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc.: Employment.

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Clinical Implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32) and -17p13 (p53) Deletions in Myeloma Patients Treated with High Dose Therapy.

Blood ◽

10.1182/blood.v104.11.334.334 ◽

2004 ◽

Vol 104 (11) ◽

pp. 334-334

Author(s):

Morie Abraham Gertz ◽

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Philip R. Greipp ◽

Mark R. Litzow ◽

...

Keyword(s):

Cox Model ◽

Multivariable Analysis ◽

Clinical Importance ◽

High Dose ◽

Therapeutic Approaches ◽

Time To Progression ◽

High Dose Therapy ◽

Dose Therapy ◽

Conventional Cytogenetics ◽

The Impact

Abstract Introduction: FISH is able to recognize chromosomal deletions and translocations with a greater sensitivity than conventional cytogenetics. Specific abnormalities have been associated with prognosis. Initial observations suggest a poor outcome for patients with -17p13.1, chromosome 13 abnormalities (Δ13) and t(4;14)(p16.3;q32). In contrast a good outcome has been shown in some series for patients with t(11;14)(q13;q32). We analyzed the value of FISH in patients receiving high dose therapy . Patients and Methods: We studied by cIg-FISH 226 patients undergoing high dose therapy at Mayo Clinic between 1/1990 and 9/2001. All patients had a pretransplant cIg-FISH done on cytospin slides from marrow aspirates for t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13.1(p53). Information was available regarding Δ13 for all patients (+ in 52%). Results: The prevalence of the abnormalities were: t(11;14)(q13;q32) 17% (n=197), t(4;14)(p16.3;q32) 13% (n=153), and -17p13.1 11% (n=168). The overall survival (OS)was significantly shortened in patients with t(4;14)(p16.3;q32) (18.2 vs. 43.3 mo, p=0.001) (figure) and patients with -17p13.1 (14.7 vs. 38.6 mo, p=.01). OS was not different for patients with the t(11;14)(q13;q32) (36.2 vs. 34.8 mo, p=ns). Likewise time to progression (TTP) was shortened in patients with t(4;14)(p16.3;q32) (8.5 vs 17.7 mo, p=.001) and -17p13.1 (8.3 vs. 16.2 mo, p=0.005). TTP was also not affected significantly by the t(11;14)(q13;q32) (20.7 vs. 14.9 mo, p=NS). To dissect the specific contribution of t(4;14)(p16.3;q32) we did a subset analysis of patients who also had Δ13, since 85% of patients with t(4;14)(p16.3;q32) are expected to have Δ13. Of 84 studied for both abnormalities 22 had both Δ13 and t(4;14)(p16.3;q32). The OS was significantly shorter in patients with both abnormalities versus those with Δ13 alone (26.6 vs. 18.2 months, p=0.001). When a multivariable analysis of the impact of Δ13 and t(4;14)(p16.3;q32) were placed into a Cox model the hazard function for t(4;14)(p16.3;q32) was greater than Δ13 (2.6 versus 1.6). Δ13 had only borderline significance in this model (p=0.06). Conclusion: We have been unable to corroborate the improved outcome after transplant for patients with t(11;14)(q13;q32). As has been reported in patients with conventional and high dose therapy -17p13(p53) and t(4;14)(p16.3;q32) have clinical importance for estimation of OS and TTP. In this patient group the t(4;14)(p16.3;q32) carried a greater adverse impact than did Δ13, and identifies a subset of patients whose time to progression is 8.5 months. These patients likely do not benefit from autologous transplant and are candidates for novel therapeutic approaches. Outcome Successful determination Patients with translocation or deletion Survival (months) with/without abnormality Time to Progression (months) with/without abnormality * p<0.01;**p<0.001 t(11;14)(q13;q32) 197 34(17%) 36.2/34.8 20.7/14.9 p53 168 18(11%) 14.7/38.6 * 8.3/16.2 * t(4;14)(p16.3;q32) 153 26(17%) 18.2/43.3 **figure 8.5/17.7 ** t(4;14)(p16.3;q32)/Δ13+ patients 84 22(26%) 18.2/26.6 8.2/12.8 * Figure Figure

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Transfusion Independence in Lower-Risk, Non-del5(q) Myelodysplastic Syndromes (LR-MDS) Among Patients (pts) Initiating Hypomethylating Agents (HMAs) While Receiving Red Blood Cell (RBC) Transfusions

Blood ◽

10.1182/blood-2018-99-116497 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 838-838 ◽

Cited By ~ 1

Author(s):

Amer M. Zeidan ◽

Weiwei Zhu ◽

Rong Wang ◽

Maximilian Stahl ◽

Scott F Huntington ◽

...

Keyword(s):

Clinical Trial ◽

Median Time ◽

Research Funding ◽

Cox Model ◽

Clinical Trial Data ◽

Trial Data ◽

Lower Probability ◽

Medicare Claims ◽

Transfusion Independence ◽

Significant Difference

Abstract Background: HMAs were approved in the U.S. for treatment of MDS in 2004 (azacitidine) and 2006 (decitabine), and are used for upfront management higher risk disease and in LR-MDS at progression or after failure or low likelihood to respond to erythropoiesis stimulating agents (ESAs). Clinical trial data suggest that 24-50% of LR-MDS pts achieve RBC transfusion independence (TI) from prior transfusion dependence (TD) with HMA therapy. Response among older pts with LR-MDS treated with HMA in a real-world setting is unclear. We have previously shown that survival of higher risk MDS pts treated with HMAs in real-life setting is much shorter than clinical trial data. We therefore examined rates of achieving TI in LR-MDS pts receiving HMAs. Methods: We identified adults >65 years old diagnosed with LR-MDS (WHO categories RA, RARS, and RCMD) in 2004-2013 from the Surveillance Epidemiology and End Results Medicare claims data. Exclusion criteria include: pts with MDS diagnosed on autopsy report or death certificate, absence of continuous Medicare Part A and B coverage or presence of HMO enrollment from 12 months prior to diagnosis through death or end of study (12/31/2014). Pts had to initiate at least one cycle of HMA, defined as 3 to 10 doses of HMA within 28 days. A gap in treatment between 14 to 28 days indicates a new cycle. Pts were assessed for their transfusion status each week throughout the study period. We measured weekly transfusion status based on receipt of RBC transfusions (observed in Medicare claims) during the current and prior 7 weeks (8 weeks total). Transfusion status was defined as: transfusion receiving (TR), pts received at least one transfusion in each period; TD, patient received ≥2 transfusions over 8 weeks, with ≥2 transfusions ≥2 weeks apart; TI, no transfusions within the 8-week period. We required pts to be at least TR at HMA initiation. We censored observations one month prior to death and 4 weeks after the end of the last HMA cycle. TI duration is defined as number of weeks between last transfusion before achieving TI and first transfusion after TI. TI ends the week that the pt receives a transfusion. Time to achieve TI as well as duration of TI were assessed with Kaplan-Meier and Cox models, adjusting for patient's demographics, health status at HMA initiation, prior hospitalization for bleeding and infection, and prior erythropoiesis-stimulating agent and transfusion use. Analysis was also conducted among the subset of pts who were TD at time of first HMA. Results: Among 336 pts with LR-MDS who initiated HMA while RBC TR, median age was 76 years (interquartile range [IQR]: 71-81) and 87.2% were non-Hispanic white. Median time to HMA initiation from diagnosis of MDS was 44.3 (IQR: 13-117) weeks. 136 (40.5%) pts achieved RBC TI, with median time of 23 (95% confidence interval [CI]: 18-28) weeks (Figure 1a). Multivariate Cox model showed pts receiving ≥3 transfusions in the 8 weeks before HMA initiation were less likely to achieve TI (HR: 0.46, p<.01). Geographic region of residence also affected time to TI, with pts in the Northeast and West having lower probability of achieving TI compared to pts in the Midwest (hazard ratio [HR]: 0.44, 95% CI: 0.24-0.80 and HR: 0.56, 0.36-0.87 respectively). Medicaid dual coverage also had a positive association with achieving TI (HR: 1.92, p=.03). Median TI duration was 50 (95% CI:26-76) weeks (Figure 1b). Among 192 pts who were TD at HMA initiation, 64 (33.3%) achieved TI, with a median time to TI of 32 (95% CI: 24-71) weeks. Median TI duration was 60 (95% CI: 23-87) weeks. TD pts of older age (>85 years) showed a higher tendency of losing TI over younger pts (age 66-69) (HR: 4.50, p=.04). Conclusions: Achieving TI is an important quality of life outcome for MDS pts. Our results indicate that a substantial portion of HMA recipients who were RBC TD or TR at initiation achieved TI status, with slightly shorter time to achieve TI for those who initiated while TR compared to TD, and no significant difference in duration of TI. Our results are limited by inability to assess for lenalidomide use and lack of ascertainment of reason of HMA initiation (progression of LR-MDS versus ESA failure). Observed rates of achieving RBC TI in LR-MDS pts utilizing HMA were consistent with clinical trials. Disclosures Zeidan: Celgene: Consultancy; Gilead: Consultancy; Pfizer: Consultancy; Incyte: Employment; Abbvie: Consultancy; Ariad: Consultancy, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy. Huntington:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Research Funding; Genentech: Research Funding; LAM Therapeutics: Research Funding; Daiichi Snakyo: Research Funding; Boehringer Ingelheim: Research Funding. Gore:Celgene: Consultancy, Research Funding. Ma:Celgene: Consultancy; Incyte: Consultancy. Davidoff:Celgene: Research Funding.

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Early Prediction of Stable MR4.5 By Achievement of 2.8 Log Reduction in BCR-ABL1 qPCR Levels at 6 Months in Patients with Chronic Myeloid Leukemia Treated with Frontline Imatinib

Blood ◽

10.1182/blood-2018-99-110135 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3022-3022

Author(s):

Aisling Nee ◽

Jeffrey H. Lipton ◽

Dennis Dong Hwan Kim

Keyword(s):

Median Time ◽

Research Funding ◽

Multivariable Analysis ◽

Imatinib Therapy ◽

Molecular Response ◽

Molecular Responses ◽

Log Reduction ◽

Disease Characteristics ◽

Univariate Analyses ◽

Tki Discontinuation

Abstract Introduction Tyrosine kinase inhibitor (TKI) therapy has dramatically improved the prognosis of CML, with life expectancy now approaching that of the general population. TKIs are, however, associated with impaired quality of life, toxicity and financial burden to the patient and economy. Treatment free remission (TFR) is achievable in approximately half of patients who attain a sustained deep molecular response (DMR), however, it is not yet fully elucidated how best to predict candidates for successful TFR attempt. It is even harder to predict which patients will achieve a sustained DMR for 2 years or longer, which is a pre-requisite for TKI discontinuation. If it were possible to identify the patients who will not achieve a sustained DMR with Imatinib, a TKI switch could be considered earlier in order to make them a candidate for TFR attempt. Aims We aimed to identify disease characteristics and molecular responses that can predict future achievement of Stable MR4.5 (defined as a reduction in BCR/ABL1 transcripts of 4.5 logs or deeper on repeated testing for 2 consecutive years) with frontline Imatinib. Patients and Methods We collected data on pre-TKI variables (baseline disease characteristics), post-TKI variables (molecular response at various timepoints) and outcomes in patients commencing frontline Imatinib in our institution from 1999 to 2014 (n=593). Statistical analysis was performed using EZR software. Univariate analysis was performed by cumulative incidence method considering competing events and Gray test. Cut-offs for continuous variables were determined by recursive partitioning (rpart). Multivariable analysis was performed using Fine-Gray model. Results With 8.9 years of median follow-up duration, the overall survival was 96.9% at 8 years. The median time to MR4.5 was 8.8 years. The rate of MR4.5 was 39.7% at 5 years and 48.3% at 8 years. The rate of Stable MR4.5 was 25.6% at 8 years. In the subset of patients achieving MR4.5, over 80% subsequently achieved Stable MR4.5 (82.4% at 8 years) (Fig. 1). The median time from achievement of first MR4.5 to Stable MR4.5 was 3.5 years. Univariate analyses of baseline variables (age, gender, disease phase, additional cytogenetic abnormalities and baseline blood counts) were performed, using rpart method to determine cut-offs for blood counts as follows: white cell count (WBC) ≥218x109/L, blast percentage ≥4%, hemoglobin (Hb) ≥88.5g/L and platelets ≥176x109/L. The only statistically significant pre-TKI variables on these analyses were WBC, blast percentage, Hb and platelet count. Univariate analyses of the following post-TKI variables were also performed: molecular response at 3, 6 and 12 months, time to complete cytogenetic response, major molecular response and MR4.5.Early molecular responses of ≥1 log reduction in transcripts at 3 months, ≥2 logs at 6 months and ≥3 logs at 12 months were tested. The following cut-offs for molecular response, as determined by rpart method, were also tested: ≥2.2 log reduction at 3 months, ≥2.8 logs at 6 months and ≥3 logs at 12 months.Univariate analysis showed statistical significance (p<0.0001) for all the post-TKI variables tested. Multivariable analyses of baseline blood counts and molecular response at 3 and 6 months were performed. The only variable that remained statistically significant was molecular response at 6 months using a cut-off of ≥2.8 log reduction in transcripts (HR 3.1, p<0.001) (Table 1). 44.4% of patients achieved ≥2.8 log reduction in transcripts at 6 months, with a rate of Stable MR4.5 at 8 years of 65.8%, compared to 17.2% for those with <2.8 log reduction at 6 months (Fig. 2). Conclusions In patients who achieved MR4.5, over 80% subsequently achieved Stable MR4.5, making them eligible for TKI discontinuation. In multivariable analysis, molecular response at 6 months was the only predictor for subsequent achievement of Stable MR4.5. Based on this data, a patient at high-risk of failing to attain Stable MR4.5 with Imatinib therapy can be identified if they fail to achieve a 2.8 log reduction or deeper within 6 months of Imatinib therapy. If a patient interested in TFR has a molecular response at 6 months of less than a 2.8 log reduction, then a switch in therapy to a second generation TKI may be considered. The optimal 6 month response to predict future Stable MR4.5 remains unclear, but our data suggest that a cut-off in transcripts of ≥ 2.8 log reduction may be a better predictor of future Stable MR4.5. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Paladin: Consultancy.

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Association of baseline perineural invasion with shorter time to progression in men with prostate cancer undergoing active surveillance: Results from the REDEEM study.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.23 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 23-23

Author(s):

Daniel M. Moreira ◽

Neil Eric Fleshner ◽

Stephen J. Freedland

Keyword(s):

Prostate Cancer ◽

Active Surveillance ◽

Perineural Invasion ◽

Cox Model ◽

Multivariable Analysis ◽

Specific Antigen ◽

Expectant Management ◽

Time To Progression ◽

Kaplan Meier

23 Background: Perineural invasion (PNI) on prostate cancer (PC) biopsies has been associated with disease upgrading among those undergoing radical prostatectomy. However, the clinical significance of PNI in men on active surveillance (AS) has been evaluated by a limited number of studies. Thus, we sought to evaluate the association of PNI with time to clinical and pathological progression in men with PC on AS. Methods: Retrospective analysis of 289 men 48 to 82 years old on AS for low-risk PC (T1c-T2a), Gleason ≤6, ≤3 positive cores, ≤50% of any core involved, prostate-specific antigen (PSA) ≤11ng/ml, life expectancy >5 years and follow-up data in the REduction by Dutasteride of clinical progression Events in Expectant Management study. Progression was divided in pathological (>3 positive cores, >50% core involvement or Gleason >6 in a repeat biopsy) or therapeutic (any treatment for PC) or both. Time to progression was analyzed with Kaplan-Meier plots, log-rank tests and Cox model adjusting for age, PSA density, percent cores involved, maximum core involvement and treatment. Results: A total of 11 (4%) patients had PNI on baseline biopsy. PNI was associated with higher tumor length and maximum core involvement (all P<0.05). PNI was not associated with patient’s age, race, PSA levels or density, percent or number of positive cores. After a median follow-up of 37 months, 125 (43%) patients developed progression. Of these, 95 (76%) patients had pathological and 30 (24%) had therapeutic progression. In univariable analysis, patients with baseline PNI had a shorter time to overall and pathological progression (HR=2.62, 95%CI=1.31-5.23, P=0.006 and HR=2.42, 95%CI=1.03-5.66, P=0.041, respectively). Similar results were obtained in multivariable analysis for overall and pathological progression (HR=2.26, 95%CI=1.10-4.68, P=0.028 and HR=2.13, 95%CI=0.88-5.13, P=0.092, respectively). Conclusions: Among patients with PC on AS, PNI is independently associated with shorter time to progression. Thus, PNI may be used to help select patients for AS and stratify them according to the risk of disease progression.

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The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2020-136256 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Maria Gavriatopoulou ◽

Andriani Boultadaki ◽

Vassilis Koutoulidis ◽

Ioannis Ntanasis-Stathopoulos ◽

Charis Bourgioti ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Research Funding ◽

Low Dose ◽

Whole Body ◽

Bone Lesions ◽

Time To Progression ◽

Symptomatic Disease ◽

Time Points

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment. Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data. RESULTS We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement. Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy. Disclosures Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

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Immunoglobulin Variable Gene Region (IGVL) Usage Correlates with Distinct Clinical Presentation in IgM Versus Non-IgM Light Chain Amyloidosis

Blood ◽

10.1182/blood-2019-121714 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1770-1770

Author(s):

Surbhi Sidana ◽

Surendra Dasari ◽

Taxiarchis Kourelis ◽

Angela Dispenzieri ◽

David L Murray ◽

...

Keyword(s):

Mass Spectrometry ◽

Binding Site ◽

Clinical Features ◽

Light Chain ◽

Research Funding ◽

Clinical Presentation ◽

Statistical Significance ◽

Organ Involvement ◽

Al Amyloidosis ◽

Gene Usage

Introduction: The clinical presentation and frequency of organ involvement are quite distinct in patients with IgM amyloidosis compared to patients with non-IgM amyloidosis, with less heart involvement and more nerve, soft tissue and lung involvement in IgM patients. It has been observed that immunoglobulin light chain variable region (IGVL) gene and gene family of the plasma cell clone impact phenotypic manifestations in AL amyloidosis, particularly organ tropism. (Kourelis et al. Blood. 2017;129). Given the variability in clinical features amongst patients with IgM vs. non IgM AL amyloidosis, we hypothesized that IGVL gene usage would be different between these two groups. Methods: Patients with newly diagnosed IgM and non-IgM amyloidosis seen at our institution from 01/2006 to 12/2015 were identified. IGVL gene usage was assessed by liquid chromatography tandem mass spectrometry (LC/MS/MS) as previously described. (Vrana et al Blood 2009;Dasari et al J of Proteome Res; Kourelis et al. Blood. 2017). Mass spectrometry data for IGVL analysis was obtained from clinically available data. LC/MS/MS was performed on available archival specimens when such data was not available clinically. Results: Patients with newly diagnosed amyloidosis who had sufficient mass spectrometry data on fat aspirate or tissue biopsy for IGVL gene usage identification were included (IgM AL, N=44 and Non-IgM AL, N=391). Clinical Features: As expected, differences were noted in baseline characteristics of patients with IgM vs. non-IgM AL amyloidosis. Patients with IgM amyloidosis were older (68 vs. 64 years, p=0.04) and more likely to have kappa as the involved light chain (34% vs. 25%, p=0.2), though the difference did not reach statistical significance. IgM amyloidosis patients had lower difference in involved and uninvolved free light chains (dFLC) (15.5 vs. 25.8 mg/dL, p=0.01) and lower NTProBNP levels (median: 1987 vs. 2655 pg/mL, p=0.02) compared with non-IgM amyloid patients. Presence of t(11;14) was less common by FISH (30% vs. 48%, p=0.1), though the difference did not reach statistical significance. Patterns of organ involvement were different, with heart involvement being less frequent in IgM patients (64% vs. 76%), while peripheral nerve (30% vs. 18%, p=0.05), soft tissue (41% vs. 21%, p=0.005) and lung involvement (7% vs. 3%, p=0.1) were more common in patients with IgM vs. non-IgM AL amyloidosis. There was no difference in liver (9% vs. 15%), kidney (50% vs. 51%) GI (23% vs. 25%) or autonomic nervous system involvement (18% vs. 14%). IGVL Gene Usage: As shown in Figure 1, IGVL usage differed across the two groups. In the lambda group, LV2-08 (14% vs. 2%, p<0.001) and LV2-14 (36% vs. 10%, p<0.001) were more common in IgM amyloid patients, while LV1-44 (0% vs. 10%, p=0.02) and LV6-57 (2% vs. 18%, p=0.004) were less common in the IgM group. There was also a trend towards less frequent involvement of LV3-01 (2% vs. 12%, p=0.07) in IgM amyloid patients. In the kappa group, KV4-01 (11% vs. 4%, p=0.04) was more common in patients with IgM amyloidosis. Correlation Between IGVL Gene usage and Clinical Features: IGVL gene usage correlated with disease characteristics and differences in the clinical presentation of patients across the two groups. LV2-14 was more commonly seen in IgM amyloid patients (above). It has been previously associated with a higher frequency of peripheral nerve involvement (Kourelis et al. Blood 2017), which was more frequent in IgM group. LV2-14 is also associated with low dFLC levels, which were noted to be lower in the IgM AL cohort. LV1-44 has been associated with higher likelihood of cardiac involvement. LV1-44 was seen less frequently in the IgM amyloid patients, who also had lower rates of cardiac involvement. LV6-57 has been historically associated with higher rates of t(11;14). It was less common in IgM AL patients, who also had lower rates of t(11;14). Conclusions: IGVL gene usage differed significantly in patients with IgM vs. non-IgM amyloidosis, correlating with differences in disease characteristics and organ involvement. This is the first study to our knowledge to report IGVL gene usage differences in IgM vs. non-IgM AL amyloidosis. Differences in IGVL gene usage may explain the distinct clinical presentation seen in IgM amyloidosis, the biology of which has so far remained poorly understood. *SS and SD contributed equally Disclosures Dasari: The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Akcea: Consultancy; Intellia: Consultancy. Murray:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding. Gertz:Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding; Celgene: Honoraria.

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