Outcome of Very Young (≤ 40 years) Patients with Immunoglobulin Light Chain Amyloidosis (AL): A Case Control Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5576-5576
Author(s):  
Jithma P Abeykoon ◽  
Miriam Hobbs ◽  
Jonas Paludo ◽  
Dirk R Larson ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Case Control Study ◽  
Years Of Life Lost ◽  
Advisory Committees ◽  
The Mean ◽  
Control Study

Abstract BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

scholarly journals Clinical Presentation and Outcomes of Patients with Light Chain Amyloidosis Who Have Non-Evaluable Free Light Chains at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3272-3272
Author(s):  
Surbhi Sidana ◽  
Nidhi Tandon ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Renal Involvement ◽  
Light Chains ◽  
Free Light Chains ◽  
Advisory Committees

Abstract Introduction: Hematologic response criteria for light chain amyloidosis (AL) requires that difference in involved and uninvolved free light chains (dFLC) be at least 5 mg/dL (or 50 mg/L). However, many patients do not meet these criteria and are often excluded from clinical trials. These patients are challenging to follow clinically as organ response takes much longer and therefore response to treatment is difficult to evaluate in the first few cycles. This study aims to evaluate patients who had non-evaluable FLC (dFLC< 5 mg/dL) at diagnosis and compare them to those who had evaluable FLC (dFLC≥ 5 mg/dL). Methods: All patients with newly diagnosed AL seen within 90 days of diagnosis at our institution over a 10-year period (2006-2015) were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up was extracted from electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to progression requiring treatment change or relapse requiring re-institution of treatment or death. PFS and overall survival (OS) were analyzed via the Kaplan-Meier method. Results: Of 1336 patients meeting inclusion criteria, dFLC at diagnosis was known in 1290. 85.4% (n=1101) had dFLC ≥ 5 mg/dL, while 14.6% (n=189) had non-evaluable FLC. Median age at diagnosis (65.2 vs. 63.9 years), gender distribution (males 56.1% vs.64.8%) and involved FLC (lambda: 72.2% vs. 72.9%) was similar in FLC < 5 mg/dL and FLC ≥ 5 mg/dL group. Cardiac (38.1 vs. 76.3%, p <0.0001) and liver (10.2% vs. 16.3%, p=0.03) organ involvement were less common in patients with non-evaluable FLC (table 1). NT-ProBNP was significantly lower in the group with dFLC < 5 mg/dL in patients with and without cardiac involvement, as was Mayo cardiac stage (table 1). A trend towards less gastrointestinal (GI) involvement (17.1% vs. 24%, p=0.09) was also seen with dFLC < 5 mg/dL. In contrast, a trend towards higher renal involvement was seen in patients with dFLC < 5 mg/dL (64.6% vs. 55.9%, p=0.08), though this was not statistically significant. Median 24 hour urine protein was significantly higher in all patients (with and without renal involvement) with dFLC < 5 mg/dL compared to dFLC ≥ 5 mg/dL group (table 1). Treatment details are listed in Table 1. ASCT (autologous stem cell transplant) was utilized more commonly in patients with dFLC < 5 mg/dL compared to patients with dFLC ≥ 5 mg/dL(43.2% vs. 26.1%, p <0.0001), including ASCT alone without chemotherapy (35.4% vs. 15.3%, p <0.0001).Rates of cardiac response (53.3% vs. 50.3%, p=0.88), and time to response (27.7 weeks vs. 35.6 weeks, p=0.67), were similar in both groups. Similarly, there was no difference in rates of renal and liver response and time taken to achieve a response (table 1). In patients with evaluable FLC, hematologic response was complete response (27.3%, n=245), very good partial response (21%, n=189), partial response (18%, n=160), no response (8%, n=74), progression (2%, n=15) and not known in 26.1% (n=216). In patients who had follow up data available, 30.6% (44/144) with dFLC < 5mg/dL experienced a relapse/progression with median PFS of 4.1 years (95% confidence interval (CI): 3 to 5.7), while 34.7% (304/875) with FLC ≥ 5 mg/dL experienced a relapse/progression with median PFS of 1.3 years (95% CI 1.1 to 1.5); p<0.0001. Median OS was higher in patients with dFLC < 5 mg/dL at diagnosis at 8.3 years compared to 2.4 years in patients with dFLC ≥ 5 mg/dL (p < 0.0001) as depicted in Figure 1. Conclusions: Patients with non-evaluable FLC at diagnosis have significant differences in organ involvement and survival compared to those with FLC ≥ 5 mg/dL at diagnosis. They have less cardiac and liver involvement and a trend towards less GI involvement, which may be secondary to low serum FLC burden and consequent less organ deposition. However, a trend towards higher renal involvement was seen in dFLC < 5 mg/dL group, with significantly higher urinary protein excretion. Loss of FLC in urine may result in lower serum FLC levels in this group. Survival was significantly better in patients with dFLC < 5 mg/dL, which may be explained by less cardiac involvement, lower cardiac stage and lower median FLC at diagnosis. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Jannsen: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; AbbVie: Research Funding; Noxxon: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2877-2877
Author(s):  
Francesca Gay ◽  
S. Vincent Rajkumar ◽  
Patrizia Falco ◽  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Case Control Study ◽  
Case Control ◽  
High Dose ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Control Study

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3150-3150 ◽  
Author(s):  
Raymond L. Comenzo ◽  
Daniel E Fein ◽  
Hani Hassoun ◽  
Christina Bello ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

scholarly journals Comparison of Different Techniques to Identify Cardiac Involvement in Immunoglobulin Light Chain Amyloidosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3182-3182
Author(s):  
Mohammed A Aljama ◽  
M Hasib Sidiqi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Strain Rate ◽  
Board Of Directors ◽  
Light Chain ◽  
Mayo Clinic ◽  
Endomyocardial Biopsy ◽  
Research Funding ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Al Amyloidosis ◽  
Advisory Committees

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Analysis Of Warfarin Drug-Drug Interactions With Antibiotics In The Ambulatory Care Setting

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1143-1143
Author(s):  
Nathan P Clark ◽  
Thomas Delate ◽  
Catherine S Riggs ◽  
Daniel M Witt ◽  
Elaine M Hylek ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Warfarin Dose ◽  
Acute Illness ◽  
Control Groups ◽  
Advisory Committees ◽  
Antibiotic Group ◽  
The Mean ◽  
Excessive Anticoagulation

Abstract Background The typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known. Methods This retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified. Results A total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0. Conclusion In the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation. Disclosures: Hylek: Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4802-4802 ◽  
Author(s):  
Christopher J. Patriquin ◽  
Austin Kulasekararaj ◽  
Régis Peffault de Latour ◽  
Jun-Ho Jang ◽  
Saskia Langemeijer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Infection Risk ◽  
Meningococcal Infection ◽  
Meningococcal Infections ◽  
Advisory Committees ◽  
Start Date ◽  
The Mean

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) patients treated with eculizumab have an increased susceptibility to serious meningococcal infections. In the largest safety data set to date, representing >10 years of postmarketing pharmacovigilance surveillance of eculizumab for the treatment of PNH, the reported meningococcal infection rate was 0.24 per 100 patient-years (PY); cumulative exposure to eculizumab in PNH was 21,016 PY (Socié G, et al. Br J Haematol. 2019). To reduce infection risk, it is recommended that PNH patients receive meningococcal vaccination ≥2 weeks prior to the first dose of eculizumab; patients vaccinated <2 weeks prior to eculizumab initiation are treated with appropriate prophylactic antibiotics (P-Abx) until 2 weeks after vaccination. However, some patients may still experience meningococcal infections, as vaccination reduces but does not eliminate the risk of meningococcal infection; thus, some physicians use long-term P-Abx in addition to meningococcal vaccination to lower infection risk. The real-world use of P-Abx is not well characterized, and their effect on the incidence of meningococcal infection is unknown. The objective of this study was to assess meningococcal infection rates in PNH patients who received eculizumab with or without P-Abx. METHODS This was a cohort study consisting of eculizumab-treated PNH patients from the International PNH Registry (NCT01374360). Eligible patients received meningococcal vaccination within 6 months prior to or up to 1-month post-eculizumab initiation; had a known birth date, sex, enrollment date, and status of P-Abx use; and were evaluable for infection during the study period. To prospectively assess the rates of meningococcal infections, the start of the follow-up period was defined as the later of the registry enrollment date or eculizumab treatment start date and the end of the follow-up period was defined as the earlier of the last eculizumab treatment follow-up date or date of the first meningococcal infection (i.e., patients were censored when they developed the first meningococcal infection after registry enrollment). To compare the demographic and disease characteristics between patients who started P-Abx and those who did not (No P-Abx), data were summarized at the later of the eculizumab start date, P-Abx start date, or enrollment date for patients with P-Abx use or at the last eculizumab treatment follow-up for No P-Abx patients. Event rates and corresponding 95% CIs were calculated for meningococcal infections for patients with and those without P-Abx using Poisson regression with an offset for the log of the treatment duration. RESULTS As of January 8, 2019, 1,815 eculizumab-treated patients were enrolled in the International PNH Registry, of whom 1,231 met all inclusion criteria for this study. Of the eligible patients, 501 received P-Abx and 730 did not. For the P-Abx and No P-Abx groups, the mean age of PNH onset (37.3 vs 36.8 y, respectively) and mean age at eculizumab initiation (44.4 vs 43.1 y, respectively) were similar. P-Abx use was higher in Europe (76.6%) than in other regions (Table 1). Both P-Abx and No P-Abx groups had similar medical event histories; the mean duration of the study period was 4.3 years (SD, 2.28 years) for the P-Abx group and 3.8 years (SD, 2.48 years) for the No P-Abx group. The mean duration of P-Abx use during the study period was 0.4 years (SD, 1.01 years). The most commonly used P-Abx was penicillin (314 of 500 patients). In total, 7 patients (3 from the P-Abx group and 4 from the No P-Abx group) experienced a meningococcal infection during the study period. In these 7 patients, the mean time from meningococcal vaccination to eculizumab initiation was 0.7 months (SD, 0.23 months) for the P-Abx group and 2.4 months (SD, 1.20 months) for the No P-Abx group. The estimated rates of meningococcal infection per 100 PY were 0.1 (95% CI, 0.0-0.4) for the P-Abx group and 0.1 (95% CI, 0.1-0.4) for the No P-Abx group (Table 2). CONCLUSIONS Rates of meningococcal infection were consistent with previously reported rates and were similar in PNH patients who received eculizumab therapy with or without P-Abx. It is important to note the small number of meningococcal infections and the limited details of P-Abx use reported in the registry. Further work will assess if patients were on P-Abx at the time of infection, and what meningococcal serotypes were identified. Disclosures Patriquin: Apellis: Consultancy, Honoraria, Research Funding; Ra Pharma: Consultancy, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Kulasekararaj:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Wilson:Alexion Pharmaceuticals Inc.: Employment. Jain:Alexion Pharmaceuticals Inc.: Employment. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

scholarly journals Difference in Involved and Uninvolved Free Light Chain (dFLC) of Less Than 1mg/DL Early Post Risk Adapted Melphalan and Autologous Stem Cell Transplantation (RA-ASCT) Predicts Renal Response at 1 Year in Light Chain (AL) Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4577-4577
Author(s):  
Sneha Purvey ◽  
Kenneth Seier ◽  
Sean M. Devlin ◽  
Josel D Ruiz ◽  
Molly A. Maloy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Organ Function ◽  
Advisory Committees ◽  
Renal Response ◽  
Hematologic Response

Background: Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival (OS) in AL amyloidosis. Achieving at least a very good partial response (VGPR) defined by a dFLC <4mg/dL is an accepted goal of therapy based on favorable outcomes, including improved renal survival (REF: Palladini JCO 2012, Palladini Blood 2014). Recently more profound clonal suppression as indicated by no evidence of minimal residual plasma cell disease (MRD) in bone marrow (BM) (Muchtar Blood 2017) and achieving dFLC <1mg/dL (Manwani Blood 2018) have shown additional benefit. While depth of hematologic response by standard criteria are important, this study assessed additional factors that influence renal response and time to renal response. Methods: All patients (pts) with AL and renal involvement (biopsy proven renal tissue diagnosis and/or 24hr proteinuria >500mg/day) undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up less than 12 months post RA-ASCT, hemodialysis prior to RA-ASCT and Waldenstrom macroglobulinemia were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise (Landau Leukemia 2013). Hematologic response was assessed at 3 and 12 months (mos) post RA-ASCT (Palladini JCO 2012) and those with less than complete response (CR) were offered consolidation therapy with bortezomib and dexamethasone (BD). All pts underwent serial organ function assessment (Palladini Blood 2014). Logistic regression models were used to assess association with renal response by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance. Results: Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 pts died within a year post RA-ASCT were excluded. Median age (range) was 61 years (44-73), M:F 49%:51%, white 90% and 34% had cardiac involvement. Median (IQR) 24 hr proteinuria pre RA-ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre RA-ASCT was 9% (IQR 2-14%). 46% pts received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11%. 46% pts received BD consolidation. Hematologic response at 3 mos post RA-ASCT was CR 44%, VGPR 29%, partial response (PR) 20% and stable disease (SD) 7%. MRD in BM by 10-color flow cytometry was assessed in 33 pts and 13 (39%) were MRD negative. dFLC <1mg/dL was achieved in 63% of pts. Renal response by 12 mos following RA-ASCT was achieved in 32 pts (53%). Median (IQR) time to renal response in these pts was 5.8 mos (5.1 - 11.3). Amongst renal responders, 50% were in CR, 53% had MRD negative BM (of 15 pts) and 78% with dFLC <1mg/dL early post RA-ASCT. In pts who achieved dFLC <1mg/dL early post RA-ASCT, 66% had renal response. By univariate analysis (Table 1) OR (95% CI) Mayo cardiac Stage (2004) II and III 0.23 (0.07-0.83, p=0.025), early post RA-ASCT dFLC <1mg/dL 3.00 ( 1.01-8.93, p=0.048), VGPR early post RA-ASCT 7.80 (1.69-36.06, p=0.009), dFLC <1mg/dL at 12 mos 7.20 (2.14-24.21, p=0.001) and CR at 12 mos 10.27 (1.14-92.26, p=0.038) were significantly associated with renal response. Neither renal stage, Mayo stage (2012), MRD negativity, melphalan dose nor consolidation was associated with renal response. By multivariate analysis (Table 2), early post RA-ASCT dFLC <1mg/dL continued to be the most significant factor predicting renal response, OR (95% CI) 4.52 (1.26-16.24, p=0.021), when adjusted for renal amyloid stage and Mayo cardiac stage (2004). Conclusion: In this single center study, we report that RA-ASCT results in renal response in more than half (53%) of the patients at 1 year. Achieving dFLC <1mg/dL early post ASCT is significantly associated with renal response. Renal response is independent of baseline proteinuria and BM plasma cells or MRD status post ASCT. Our study supports that pathologic entity in organ damage is not the plasma cells but rather light chains. Further studies using dFLC <1mg/dL should be evaluated in organ response. Mass spectrometric light chain monitoring may even be more sensitive and could potentially serve as a non-invasive way to measure disease burden. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4606-4606
Author(s):  
Neeraj Y Saini ◽  
Romil Patel ◽  
Ankur Varma ◽  
Qaiser Bashir ◽  
Omar Hasan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Castleman Disease ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Advisory Committees ◽  
Entire Cohort ◽  
The Mean

Abstract Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

scholarly journals Changes in Uninvolved Immunoglobulins during Multiple Myeloma Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3251-3251
Author(s):  
Praful Ravi ◽  
Shaji Kumar ◽  
Wilson I Gonsalves ◽  
Francis K Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Treatment Response ◽  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Advisory Committees ◽  
Percentage Difference ◽  
Lower Likelihood

Abstract Background Suppression of uninvolved immunoglobulins is a common finding in multiple myeloma and the preservation of uninvolved immunoglobulins at diagnosis is associated with improved progression-free and overall survival. However, little is known about the impact of myeloma treatment on levels of uninvolved immunoglobulins, and the link between changes in uninvolved immunoglobulins during therapy and treatment response, disease progression and survival. Methods We identified patients who received therapy for newly diagnosed multiple myeloma at our institution between 2001 and 2014, and who had data available on absolute lymphocyte count (ALC) and quantitative uninvolved immunoglobulins (Ig) before commencing treatment. The ALC and levels of uninvolved Ig after 4 cycles of therapy were abstracted from the electronic medical record; patients who switched or stopped treatment, or died, before this time point were excluded. To assess change in ALC, the percentage difference in ALC between baseline and 4 cycles was calculated; for uninvolved Ig, the average of the percentage difference between baseline and 4 cycles for each uninvolved Ig (IgA and IgM for IgG myeloma, IgG and IgM for IgA myeloma, IgG and IgA for IgM and IgD myeloma, and IgG, IgM and IgA for light-chain only myeloma) was calculated. Treatment response at 4 cycles was retrospectively assigned according to International Myeloma Working Group criteria. Time to treatment failure (TTF) was defined as time from start of initial therapy to start of next line of therapy or death (if no additional treatment was received). A landmark analysis was used to calculate overall survival (OS) from the date of follow-up after 4 cycles of therapy. The Kruskal-Wallis, Chi-Square, and log rank tests were used to detect differences in medians, proportions, and survival times respectively. Results A total of 421 patients were included in this analysis. The median age was 63 years (range 33-91), 254 patients (60.3%) were male and median follow-up was 6.5 years (95% CI 5.6-7.3); the vast majority of patients had IgG (n=247 [58.7%]), IgA (n=98 [23.3%]) or light-chain only myeloma (n=68 [16.2%]). First line therapy comprised of pulse-dose dexamethasone (DEX, n=92 [21.9%]), lenalidomide-dexamethasone (RD, n=176 [41.8%]), bortezomib-dexamethasone (VD, n=22 [5.2%]), bortezomib-cyclophosphamide-dexamethasone (VCD, n=84 [20.0%]), and bortezomib-lenalidomide-dexamethasone (VRD, n=47 [11.2%]). Across the entire cohort, the median change in ALC and uninvolved Ig after 4 cycles of treatment was -11.0% (range: -92.7 to +718.8) and +9.0% (-77.7 to +1094.4) respectively; treatment with VCD was associated with the greatest median declines in ALC (DEX: -0.1%; RD: -9.9%; VD: -20.8%; VCD: -40.9%; VRD: -15.3%) and uninvolved Ig (DEX: -0.5%; RD: +15.5%; VD: +44.0%; VCD: -14.0%; VRD: +76.0%, both p<0.001). Conversion from suppression to normalization of the primary uninvolved Ig (IgA in IgG myeloma, and IgG in all other myeloma types) after 4 cycles was seen more frequently with the use of RD (13.1%) and VRD (12.8%) compared to DEX (4.7%), VCD (1.3%), or VD (4.8%), χ2=21.8, p=0.040. When considering only patients in whom the primary uninvolved Ig remained suppressed between baseline and 4 cycles, a ≥25% reduction in the primary uninvolved Ig occurred more frequently with the use of DEX (51.5%) and VCD (34.5%) compared to RD (24.8%), VD (23.5%) or VRD (25.7%), χ2=15.1, p=0.005 (Table 1). Although an average reduction in uninvolved Ig between baseline and 4 cycles (ΔIg<0) was independently associated with a lower likelihood of achieving very good partial response (VGPR) of better on multivariate analysis adjusting for age, sex and treatment regimen (OR=0.40 [0.24-0.63], p<0.001), there were no differences in TTF (2.0yrs vs. 2.0yrs, p=0.783) or OS (8.0yrs vs. 8.0yrs, p=0.721) between patients with ΔIg<0 (n=169) and those with ΔIg≥0 (n=222). Conclusions Myeloma treatments produce differential impacts on immune parameters, with VCD causing the greatest reduction in lymphocytes and uninvolved Ig, implying general targeting of plasma cells, in comparison to lenalidomide, which appeared to be more tumor-specific with relative sparing of lymphocytes and uninvolved Ig. While an average decrease in uninvolved Ig was an independent predictor of a lower likelihood of achieving VGPR or better after 4 cycles of therapy, it was not associated with a shorter TTF or poorer OS. Disclosures Kumar: BMS: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; Millennium: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Dispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding.

Infectious Complications Among Individuals with Monoclonal B-Cell Lymphocytosis (MBL): A Prospective Case-Control Study of Newly Diagnosed Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3903-3903
Author(s):  
Jonathan Moreira ◽  
Kari Rabe ◽  
James R Cerhan ◽  
Curtis A. Hanson ◽  
Timothy G Call ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Local Community ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Control Study

Abstract Abstract 3903 INTRODUCTION: Monoclonal B-Cell Lymphocytosis is an asymptomatic hematologic condition characterized by the presence of small populations of clonal B-cells in the blood or bone marrow occurring in 3–5% of the general population over age 40. Although MBL is considered the precursor state to CLL and other sub-types of indolent non-Hodgkin Lymphoma, most individuals with MBL will not develop a B-cell malignancy. It is unknown, however, whether individuals with MBL may be at risk for other adverse outcomes associated with CLL, such as increased risk of infection. To explore this aspect, we evaluated the risk of hospitalization for infection among patients with clinically recognized MBL and compared this to a cohort of general medicine patients and a cohort of CLL patients. METHODS: The Mayo Clinic Rochester (MCR), a tertiary referral center in rural southeastern Minnesota, is also the primary hematology center for southeastern Minnesota, northern Iowa, and western Wisconsin. There are no metropolitan areas or hematology specialty centers within a 50 mile radius. To explore the natural history of infection in a local, community dwelling cohort of individuals with clinically identified, CLL-phenotype MBL, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed MBL seen in the MCR Hematology Division between January 1999 and December 2009. Analysis was limited to MBL cases who resided within 50 miles of MCR. The comparison cohort consisted of 689 adult patients also resided within 50 miles of MCR who were seen for a general medical examination between September 2002 and December 2009 and who were enrolled as controls in a case-control study of non-Hodgkin lymphoma. Rates of infection among individuals with MBL were also compared to a cohort of 174 patients with newly diagnosed CLL diagnosed in the same time interval and who resided within 50 miles of MCR. All hospitalizations in these 3 groups were audited to document hospitalization with infection including cross-referenced with the electronic Mayo Clinic infection database, which contains all culture results obtained from hospitalized patients at MCR. Serologies and viral assays (e.g. CMV viral load) were also reviewed. Patients whose cultures were negative but who were given a clinical diagnosis of infection (e.g. pneumonia) and who were treated with a full course of antibiotics were considered to have a culture negative infection. Among the cases, only hospitalizations after CLL or MBL diagnosis were considered. RESULTS: In May 2010, there were 524 individuals in the Mayo Clinic MBL/CLL Database with the diagnosis of CLL-phenotype MBL made between January 1999 – December 2009. Of these, 154 (29%) patients resided within a 50 mile radius of Mayo Clinic and were considered a local, community-based cohort of MBL patients. Median age at MBL diagnosis for these 154 patients was 70 years (range 45–94). After median follow-up of 4.2 years (range 0.3–10.6 years), 25 (16%) individuals with MBL were hospitalized with infection as compared to 20/689 (3%) individuals in the control population (odds ratio MBL relative to control=6.5; p<0.001) and 32/174 (18%) in the cohort of patients with newly diagnosed CLL (OR MBL relative to CLL=0.9; p=0.61) (Figure 1). The 25 MBL patients hospitalized for infection were hospitalized a total of 39 times (median 1 hospitalization for infection per individual). A specific infectious organism was identified by cultures or serologies in 8/39 (21%) hospitalizations among individuals with MBL, 10/27 (37%) hospitalizations for infection among controls, and 60 (63%) of the 89 hospitalizations for infection in CLL cases. Finally we performed a pooled multivariable analysis of all patients (n=1017) adjusting for age, sex, presence of MBL, diagnosis of CLL, and whether patients with CLL or MBL received treatment for CLL during follow-up. All factors were independently associated with risk of hospitalization for infection [Age (per year, OR=1.02, p=0.02), sex (male, OR=2.6, p=0.001), presence of MBL (OR=3.3, p<0.001), diagnosis of CLL (OR=3.0, p=0.002), and treatment for CLL (OR=3.3, p<0.001)]. CONCLUSIONS: In this cohort study, patients with newly diagnosed clinical-MBL had a 6.5 fold risk of hospitalization for infection relative to the control cohort. MBL was an independent risk factor for hospitalization for infection after controlling for age, sex, and treatment. Disclosures: Zent: GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

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