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Abstract Background: High dose therapy with autologous stem cell rescue has been shown to prolong survival in patients with multiple myeloma in randomized controlled trials. However, most of the prospective studies have included younger patients, usually 65 or less. It is important to have a better understanding of the outcome of transplantation in the older patients given the median age of onset of myeloma of 65 years. We retrospectively reviewed our institutions experience with high dose therapy for patients over 70 years. Methods: We identified 35 patients with multiple myeloma, from the transplant database, who were at or over the age of 70 at the time of their high dose therapy. We matched these patients to 70 patients (two matches for each patient), based on stage at transplant (primary refractory, plateau phase, relapse off therapy, or relapse on therapy), Durie Salmon stage, high or low labeling index, conventional cytogenetics (abnormal vs normal), presence or absence of circulating plasma cells at time of transplant, and whether cyclophosphamide was used as part of mobilization in that order of priority. Results: The median age of the two groups were 55.3 (Range 37.3–64.8) and 71.7 (Range 70–75.8) years at the time of transplant. The median time to transplant from diagnosis was similar (6.4 for the older patients compared to 6.9 months for the other, P = NS). Ten of the 35 older patients received reduced dose melphalan (140 mg/2)) compared to 3 patients in the control group; P < 0.01. The median follow up from transplant was 10.1 months for the older patients compared to 18 months for the control group. The overall response rate was similar for the two groups (97.1% for the older patients compared to 95.5 for the control group). Eleven (31%) of the older patients and 17 (24%) of the control patients achieved a CR (P = NS). The post transplant progression free survival estimate at 1 year post transplant was 65.3% for the older patients compared to 66% for the control group (P = 0.3)The two year estimated overall survival from transplant was similar in the two groups; 58% for the older patients compared to 67% for the control group. The overall survival from diagnosis was similar for the two groups (P = 0.6). The median number of days hospitalized was 9 days for the older population compared to 5 days for the control group (P = 0.37). Four patients died within the first one hundred days, one (3%) among the older patient group and 3 (4.3%) in the control group. Conclusions: High dose therapy and autologous stem cell transplantation is feasible in selected patients with multiple myeloma over 70 years. It is likely that these older patients were selected based on their overall performance status, a factor that is difficult to analyze in this retrospective review. Nearly 70% of the elderly patients received full dose melphalan for conditioning (200 mg/m2). The toxicity of transplant as well as the outcome appears to be very similar to the younger patients. Patients with multiple myeloma should not be excluded from high dose therapy solely on the basis of their chronological age.

Abstract Background: Copper deficiency is an established cause of hematological abnormalities, traditionally described in malnourished infants and persons with malabsorption or short bowel syndromes, particularly those requiring long-term parenteral nutrition. With the recent increase in bariatric (weight reduction) surgery, acquired copper deficiency may be increasing in incidence but the diagnosis is frequently delayed. Methods: To outline the natural history of copper deficiency we searched the Mayo Clinic database and our heavy metals laboratory for patients diagnosed with low serum copper during the years 1974–2005. Copper deficiency was defined as a serum level < 0.75 μg/ml. Results: We identified 123 patients with a low serum copper. 77 patients were excluded as the the hypocupremia was either transient or due to other factors such as Wilson’s disease. The remaining 46 patients were all symptomatic. 25 patients had hematological abnormalities, 20 of these patients also had neurological involvement. 5 had isolated hematological manifestations and 21 patients had isolated neurological findings, most commonly myeloneuropathy. 13 presented with anemia and leukopenia, 5 with pancytopenia, 6 with anemia and 1 with isolated neutropenia. In 10 of the 25 cases, a secondary contributing cause for the hematological findings was identified. These included possible anemia of chronic disease (4), renal insufficiency (2), iron deficiency (1), B12 deficiency (1), GI hemorrhage (1), and splenomegaly (1) while copper deficiency was the only identifiable cause in the remaining 15 patients. Hematological parameters at diagnosis are outlined in the table. 15 of the 25 patients with hematological manifestations had a history of GI surgery, including 6 patients who had bariatric surgery. The median time from surgery to diagnosis was 11.5 years (range 8 months - 45 years) and was shorter for bariatric surgery (10 years, range: 8 months - 25 years) than for non-bariatric surgery (18 years, range: 2–45 years). 1 patient had a history of excessive zinc ingestion, 1 had malabsorption secondary to chronic pancreatitis and 1 patient had celiac disease. In 7 cases, no explanation was found. 24 of 25 patients received treatment with oral or intravenous copper, 5 were lost to follow up. In 16 patients the hematologic parameters either improved significantly or normalized, while in the remaining 3 patients there was no improvement. Factors that may explain the lack of response in these patients included splenomegaly (1), renal insufficiency (1) and multiorgan illness (1). Conclusion: Copper deficiency is an increasingly frequent cause of hematological abnormalities, and can manifest with refractory cytopenias with or without associated neurological symptoms. Thrombocytopenia is relatively rare. Previous GI surgery, especially bariatric surgery, appears to be a major causative factor. Most patients will have an improvement in hematological parameters after copper supplementation. Recognition of copper deficiency is therefore assuming greater importance in view of the increasing frequency of bariatric surgery, ease of treatment and potential for irreversible neurological damage if diagnosis is delayed. Hematologic parameters at diagnosis HgB (g/dL) MCV (fL) WBC (x109/L) ANC(x109/L) Plts(x109/L) Median 10.6 99 3.0 1.25 215 Range 7.9-13.6 83.9-114.1 1-5.6 0.18-4.0 54-554

Abstract Background: Copper deficiency is increasingly being diagnosed in adults with malabsorption syndromes, especially following GI surgery such as gastric and bowel resections and bariatric surgery. The most common hematologic manifestations are refractory anemia and neutropenia and patients have been misdiagnosed as having myelodysplasia. Certain findings on bone marrow examination are felt to be characteristic for copper deficiency such as maturation arrest in the myeloid lineage, vacuolization of the erythroid and myeloid precursors and ringed sideroblasts. Methods: We reviewed all cases of copper deficiency diagnosed at the Mayo Clinic from 1974 – 2005. We also reviewed all cases of low serum copper (< 0.75 μg/ml) identified in our heavy metals laboratory. Results: 123 patients with hypocupremia were identified. 77 patients were excluded as the hypocupremia was either transient or due to other factors such as Wilson’s disease. Twenty-five patients had hematologic manifestations, including anemia and leukopenia (13), isolated anemia (6), pancytopenia (5), and isolated neutropenia (1). Eighteen patients had a bone marrow biopsy. We were able to retrieve and review bone marrow slides in 11 cases. The bone marrow examination findings are shown in the table. The marrow cellularity was decreased in four cases. All cases had granulocytic hypoplasia but preserved megakaryopoiesis. Nine cases had relative erythroid hyperplasia. All but one bone marrow had cytoplasmic vacuoles in pronormoblasts and myelocytes. Increased iron within macrophages was seen in 9 cases and increased iron in plasma cells was noted in 8 cases. This was especially prominent in the cases with low peripheral white blood count. Ringed sideroblasts were seen in 4 cases and were more commonly seen in anemic patients. The initial bone marrow examination commonly suggested toxic effect (drugs or alcohol), myelodysplasia or were non-diagnostic. Conclusion: We have described the bone marrow findings in 11 copper deficient patients with abnormal blood counts. None of these patients was suspected of copper deficiency based on the initial marrow examination. The initial impression was commonly toxic effect due to the presence of cytoplasmic vacuolization. Patients with ringed sideroblasts were suspected of having MDS. Copper deficiency should be considered in patients with cytopenias and the described bone marrow findings, especially if there is evidence of malabsorption or a history of GI surgery such as gastric resection or bariatric surgery. Bone marrow findings Patient Cellularity Ery/gran/meg Vacuoles Iron (mø/PC) RS Hgb/Plt WBC/ANC nl: normal, 0: absent, Ery/gran/meg: erythro-/granulo-/megakaryopoiesis, Iron (mø/PC): Iron in macrophages and plasma cells, RS: Ringed sideroblasts 1 ↓ ↑/↓/nl Yes ↑/↑ No 11.3/203 3.2/1.1 2 Nl ↑/↓/nl Yes 0/0 No 11.4/192 5.6/4.0 3 Nl ↑/↓/nl No ↑/0 No 10.6/95 3.0/2.2 4 ↓ ↑/↓/nl Yes ↑/↑ No 13.6/128 4.2/0.92 5 Nl ↑/↓/nl Yes ↑/↑ 10% 9.8/215 1.4/0.6 6 ↓ ↑/↓/nl Yes ↑/↑ No 7.9/292 1.8/0.18 7 Nl ↑/↓/nl Yes ↑/↑ No 10.6/280 2.7/1.4 8 Nl nl/↓/nl Yes ↑/↑ 20% 8.1/330 1.5/0.24 9 Nl ↑/↓/nl Yes ↑/↑ <1% 9.4/252 1.3/0.25 10 ↓ Nl/↓/nl Yes 0/0 No 10.5/167 2.4/1.67 11 Nl ↑/↓/nl Yes ↑/↑ yes 12.5/224 4.2/3.9

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