Hogan, William J.

Abstract We previously have reported that autograft absolute lymphocyte count (A-ALC) is a possible prognostic factor for survival after autologous peripheral blood stem cell transplant (ASCT) for myeloma (MM). Factors affecting A-ALC in MM are unknown. We hypothesize that method of stem cell mobilization, hematopoietic growth factor (HGF) vs. HGF+Cytoxan chemotherapy (C+HGF), directly affects A-ALC collection. 191 consecutive MM patients between 1994 and 2004 were analyzed retrospectively. Patients generally were mobilized with C+HGF prior to 2003. Thereafter, C+HGF was reserved largely for those with ≥4% circulating peripheral blood plasma cells (PC), a negative prognostic indicator. No patients were transplanted in disease relapse or refractory disease. Patients also were matched for age, sex, β2-microglobulin, conventional cytogenetics, LDH, c-reactive protein, number of prior therapies, plasma cell labeling index (PCLI), pre-mobilization ALC, and % bone marrow (BM) PC. The groups HGF (n=80) and C+HGF (n=111) differed with respect to the conditioning regimen (p < 0.0001), and presence of (≥4%) circulating peripheral blood PC (p<0.005). The primary end-point of the study was to assess the correlation between HGF vs C+HGF, and A-ALC. The secondary endpoint was to determine if HGF vs C+HGF affected survival post-ASCT. Patients mobilized with HGF had a higher A-ALC compared to those mobilized with C+HGF [0.764 x 109 lymphocytes/kg (range: 0.146–1.803) vs. 0.212 (range: 0.016–1.26), p<0.0001]. No association was identified between A-ALC and conditioning regimens (p = 0.19) and PC (p = 0.31). Median overall survival (OS) and progression-free survival (PFS) were longer in those mobilized with HGF vs. C+HGF (not reached vs. 48 months, p<0.0150; not reached vs. 21 months, p<0.007, respectively). Multivariate analysis demonstrated that age ≥50 vs age ≤50 (p<0.05) and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0397) were independent predictors of OS. Factors influencing PFS in the multivariate analysis included circulating PC ≥4% vs <4% (p<0.0157), PCLI ≥ 1% vs PCLI ≤ 1% (p<0.0107), and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0042). On multivariate analysis, the method of stem cell mobilization and the conditioning regimen did not have a statistically significant effect on either OS or PFS. We hypothesize that the differences in PFS and OS seen between the HGF vs C+HGF mobilization groups are mediated through the A-ALC. These data suggest that mobilization regimens should not only collect CD34+ stem cells, but also be optimized to collect an A-ALC target which may impact on PFS and OS post-ASCT.

Abstract Introduction: We previously reported that serum cardiac biomarkers are among the most powerful predictors of overall survival. This observation was based on outcomes of more than 300 patients with primary systemic amyloidosis (AL) receiving either low dose chemotherapy or high dose chemotherapy with peripheral blood stem cell transplant (PBSCT). Not all institutions use the N-terminal pro-brain natriuretic peptide (NTproBNP) assay, but rather the B-type natriuretic peptide (BNP) assay. We therefore determined the relative utility of BNP in patients with AL undergoing PBSCT and up-dated our results using our NTproBNP-troponin T staging system. Methods: Between 4/10/96 and 2/24/05, 164 patients with AL undergoing PBSCT had measurements of serum cardiac biomarkers. All BNP measurements were done on fresh serum (Biosite Inc., San Diego). The NTproBNP (Roche Diagnostics, Indianapolis, IN) and troponin T (TnT) (Roche Diagnostics, Indianapolis, IN) measurements were done on either stored serum or on fresh samples as previously reported. Follow-up for patients was through March 2005. Results: Between 5/1/03 and 2/15/05, 72 patients had BNP measurements pre-transplant. The median value was 167 pg/ml (range 5 to 7739). Forty-two of these patients also had an NTproBNP measured. There was good agreement between the two tests in the 42 patients that had both measurements (rho 0.823, p<0.0001). To further test the relationship between the two tests, we evaluated the correlation between BNP and NTproBNP using 204 simultaneous measurements from 106 patients (rho=0.89, p<0.0001). Next, we tested the prognostic utility of BNP. Using a cut-off point of 120 pg/L (the upper limit of normal for women over the age of 70 and the 50th percentile of all measurements in our data set), we found that BNP was prognostic for survival post-transplant. It was independent of TnT values, and patients could be divided into 3 risk categories using these two measurements (low risk if both values were low, high-risk if both were high, and intermediate if either was high). This system was highly predictive of overall survival (Figure A). We next compared the BNP-TnT staging system to our previously reported NTproBNP-TnT staging system in the 42 patients that had all 3 values pre-transplant. The correlation between the two staging systems was excellent (rho=0.91, p<0.0001). Follow-up for the 100 patients who had been reported previously is now 26.9 months. As shown in Figure B, the NTproBNP-TnT system predicts for overall survival post transplant. Conclusions: Serum levels of cardiac biomarkers are invaluable prognostic markers in patients with AL. Preliminary data would suggest that a BNP-TnT system is as useful as the NTproBNP-TnT system. Risk thresholds: BNP <120 pg/ml; TnT <0.035 ng/ml; NT-proBNP < 332 pg/ml BNP-TnT statisfaction: low risk, both low; high risk, both high; intermediate, either high. NT-proBNP-TnT satisfaction: low risk, both low; high risk, both high; intermediate, either high. Risk thresholds: BNP <120 pg/ml; TnT <0.035 ng/ml; NT-proBNP < 332 pg/ml BNP-TnT statisfaction: low risk, both low; high risk, both high; intermediate, either high. NT-proBNP-TnT satisfaction: low risk, both low; high risk, both high; intermediate, either high.

Abstract Introduction: The Bone Marrow Transplant Program at Mayo Clinic (Rochester, Minnesota) developed a multidisciplinary approach (involving physicians, nurses, pharmacists, dietitians, and financial specialists) for outpatient management of patients undergoing stem cell transplantation. This approach uses an electronic ordering system for diagnostic tests and chemotherapy to minimize medical errors. Table. Patient Characteristics (N=716) Characteristic Value Male, no. of patients (%) 426 (59) Age, median (IQR), y 59 (53–65) Creatinine, median (IQR), mg/dL 1.0 (0.9–1.2) b2-Microglobulin, median (IQR), mcg/mL 2.5 (1.9–3.7) Gammopathies, no. of patients (%) Measured by serum immunofixation or immunoelectrophoresis IgA 148 (21) IgG 414 (58) IgM 6 (1) IgD 12 (2) Light chain 83 (12) Biclonal 6 (1) None 47 (7) Measured by urine immunofixation or immunoelectrophoresis k light chain 402 (56) l light chain 226 (32) Biclonal 1 (0) None 79 (11) Not performed (anuric) 8 (1) Status at stem cell transplant, no. of patients (%) Untreated 4 (1) Plateau 436 (61) Primary refractory 113 (16) Relapse after therapy 93 (13) Relapse during therapy 70 (10) Characteristic Value CD34+ cells, median (IQR), ×106/kg Collected, no. 10.0 (7.6–12.6) Infused, no. 4.7 (3.9–6.2) Sessions of apheresis, median (IQR) 3 (2–5) Engraftment, median (IQR), days after transplantation Neutrophils, 0.5×109/L 13 (12–15) Platelets, 50×109/L 16 (14–22) Duration of hospitalization, median (IQR), d 4 (0–10) Abbreviation: IQR, interquartile range. Results: During a 45-month period after implementation of the program (2005-Sept 2007), the day-100 survival rate was 99.5% for low-risk myeloma patients (transplantation during first plateau; n=202) and 97% for high-risk myeloma patients (refractory, relapsing or second or greater plateau; n=71). The overall day-100 survival rate was 99%(270/273). Analysis of hospitalization trends since inception of the program showed that 39% of patients completed the transplant procedure as outpatients. The median duration of hospitalization for all patients was 4 days; age and serum creatinine levels were predictive of the need for and duration of hospitalization Conclusion: Outpatient stem cell transplantation is feasible for patients with multiple myeloma with a therapy mortality of 1%. Nearly 40% of our patients completed the procedure without hospitalization. Age and serum creatinine levels predicted a higher likelihood of hospitalization. Implementation of out patient transplant requires affordable housing in the community since many third party payers do not support hotel costs despite the reduction of hospital days. The hospital physical plant and patient registration process has to support use of designated hospital rooms for purely out patient practice. The transplant team must have process owners to standardize across all disease categories collection protocols, conditioning regimens, infusion SOP’s and post infusion supportive care guidelines for standard antibiotics, narcotics, laboratory work and transfusion thresholds. A care team meeting between physicians, nursing, dietary, pharmacy, business office, data base and appointment coordinators is essential to coordinate all the multidisciplinary efforts. Kaplan-Meier curve shows the percentage of patients remaining in the hospital through time t, stratified on the basis of age greater than or less than or equal to 65 years Kaplan-Meier curve shows the percentage of patients remaining in the hospital through time t, stratified on the basis of age greater than or less than or equal to 65 years Kaplan-Meier curve shows the percentage of patients remaining in the hospital through time t, stratified on the basis of creatinine greater than or equal to or less than 1.5mg/dL Kaplan-Meier curve shows the percentage of patients remaining in the hospital through time t, stratified on the basis of creatinine greater than or equal to or less than 1.5mg/dL

Abstract Background : Myelofibrosis (MF) is characterized by progressive bone marrow dysfunction, extramedullary hematopoiesis, massive splenomegaly, elevated levels of inflammatory cytokines, severe constitutional symptoms, cachexia and premature death. INCB018424 is a potent, selective inhibitor of JAK 1 and 2 which has demonstrated impressive clinical activity in the early portion of a phase 1/2 study in patients with PMF and Post-PV/ET MF. Methods : Following the initial dose escalation phase with a BID schedule (N=11), both twice daily (10 mg BID to 25 mg BID, N=56) and once daily (25 mg QD to 200 mg QD, N= 37) dose regimens were explored. Endpoints included spleen size assessed by manual palpation, constitutional symptoms assessed using the Modified Myelofibrosis Symptom Assessment Form (MFSAF) and JAK2 allele burden. Exercise capacity is being assessed using the Six Minute Walk Test (6MWT), and body mass and composition are being assessed using standard methods. Safety was assessed by collection of adverse events and monitoring of laboratory data. Results : Over 100 patients are currently enrolled in the study, with a mean exposure to drug of > 5 months. Twenty percent of patients have received INCB018424 for > 9 months. INCB018424 is associated with a rapid reduction of splenomegaly in over 93% of patients from a mean baseline spleen size >20 cm, with 50% or greater reduction being observed in 35% of patients dosed with 10 mg BID or 50 mg QD, and 59% of patients dosed with 25mg BID regimens. These declines nearly always occur within the first month of therapy, with further, slower decreases often observed thereafter. In responding patients, spleen size reduction persists for the duration of therapy (currently up to one year follow-up). Constitutional symptoms are reported with high frequency in the study population as assessed by the MFSAF: night sweats, pruritis and fatigue were reported by >60%, >45% and >90% of patients respectively. Improvements in self-assessed symptom scores (mean % improvement of 40% to 60%) occurred by the first assessment at week 2. Activity limitations are also reported by a high proportion of MF patients; 70% of respondents reported impaired ability to exercise or get around, with a mean score >5 on the 11-point MFSAF scale; INCB018424 therapy was associated with rapid (within 2 weeks) and marked (40% or more) improvement in self-assessed score. There was a dose-dependent weight gain, most pronounced in patients with the lowest body mass index (BMI) values at baseline. Profound reductions in inflammatory cytokines were observed by the first evaluation at week 2 in virtually all patients, and were maintained during therapy. INCB018424 is generally well tolerated with the primary toxicity being dose-dependent grade 3 or 4 reversible thrombocytopenia which occurred in 0%, 18% and 32% of patients dosed with 10 mg BID, 50 mg QD or 25 mg BID. Conclusions : INCB18424 shows unprecedented and durable clinical efficacy in reducing spleen size and improving constitutional symptoms in patients with MF. Results from proactive dose modification regimens, assessments of exercise capacity, MRI-based spleen volume assessment and body composition determination will be presented.

Abstract The infused autograft absolute lymphocyte count (A-ALC) is an independent prognostic factor for survival after autologous hematopoietic stem cell transplant (AHSCT) in non-Hodgkin’s lymphoma (NHL). Previous studies have shown that A-ALC directly correlates with the peripheral blood absolute lymphocyte count (PC-ALC) at the time of apheresis collection. However, factors affecting the PC-ALC at apheresis remain undefined. We hypothesized that one possible factor impacting PC-ALC may be the time interval from last chemotherapy to stem cell collection (TILC). Data from 160 patients who underwent AHSCT for treatment of relapsed NHL at Mayo Clinic between 1993 and 2001 were collected and analyzed. The primary end point of this study was correlation between TILC and PC-ALC, and our analysis revealed a strong correlation (r = 0.67, p < 0.0001). Further analysis revealed higher PC-ALC numbers in patients with TILC ≥ 60 days versus TILC < 60 days (median of 7.44 x 109/L in the ≥ 60 day group versus 3.87 x 109/L in the < 60 day group, p < 0.0001). Both the median overall survival (figure below) and the progression-free survival were longer in the TILC ≥ 60 days group versus the TILC < 60 days group (76 versus 21 months, p < 0.0037; 76 versus 11 months, p < 0.018, respectively). These findings were independent of other prognostic indicators for relapsed NHL patients undergoing APHSCT. The data supports our hypothesis that TILC affects PC-ALC and survival post-AHSCT in NHL. Figure Figure

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.

7526 Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.

7053 Background: The revised International Prognostic Scoring System (IPSS-R) aids in prognosticating MDS. The percentage (%) of blasts in the bone marrow is one of the major determinants of the scoring system. The aspirate blast % is utilized as the standard of care, but there could be discrepancies in the blast % reported by the aspirate and the biopsy. We aim to study the possible use of bone marrow biopsy blasts in MDS-EB in calculating IPSS-R. Methods: The MDS database was reviewed for cases of MDS-EB after due IRB approval. We calculated IPSS-R scores based on the aspirate blast % (IPSS-RAsp) and biopsy blast % (IPSS-RBx). The biopsy blast % was reported morphologically or by the CD34 stain. Whenever a range was reported the highest value was utilized as the blast %. Suboptimal aspirates were excluded from the study. The overall survival (OS) was determined by IPSS-RAsp, IPSS-RBx and IPSS-R highest blast (IPSS-RHi). OS estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Uno’s concordance statistic was used to compare all 3 risk scoring systems. Results: Of 1322 patients, 431 (33%) cases were identified with MDS-EB; out of which 173 cases had both blasts reported in the biopsy and the aspirate. Out of 173 cases, 35 (20%) had MDS-EB1, and 61 (35%) had MDS EB-2 based on both biopsy and aspirate (concordant cases). Seventy seven (45%) patients changed from EB-1 to EB2 or vice versa based on the biopsy blast (44/77 (57%) cases were upstaged). The OS outcomes based on the IPSS-RBx biopsy showed a clear and meaningful separation with median OS decreasing with increased risk but IPSS-RAsp and IPSS-RHi did not (Table). We compared the 3 models for observed OS differences using the Uno model and there was no statistically significant difference. Conclusions: IPSS-RBx (but not IPSS-RAsp and IPSS-RHi) identified prognostic groups for OS with median OS decreasing with increased risk. The small sample size may have led to an insignificant effect on model power by Uno model. This finding needs to be validated by other centers. [Table: see text]