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e14097 Background: Signet ring cell carcinoma accounts for less than 1% of all colon cancers. We examined the clinical pathological features and prognosis of signet ring cell carcinoma of colon Met...

9135 Background: End of life (EOL) care in cancer pts is becoming more aggressive over the years. Utilization of palliative care services (PCS) may decrease aggressive care in terminally ill cancer...

e14092 Background: Lymph node ratio (LNR) is the quota between the number of lymph node metastasis and assessed lymph nodes. It is prognostically significant in stage III colon cancer but is less d...

9138 Background: Hodgkin lymphoma (HL) is a very treatable disease that is known to have a bimodal age distribution. Unlike the younger patients,elderly patients with HL have a prognosis which is s...

554 Background: Primary non-Hodgkin lymphoma (NHL) of the colon is rare. There are no randomized controlled trials describing treatment outcomes for this tumor. We provide the largest descriptive study of this tumor to date. Methods: Retrospective analysis of 109 patients diagnosed with primary non-Hodgkin lymphoma of the colon from 1995 to 2008 was done via the Veteran's Affairs Central Cancer Registry. By definition, all cases presented with a lymphomatous involvement of the colon as the first manifestation of their disease with no previous diagnosis of NHL of any type or site. Demographic, staging, histology, treatment, and outcome data was recorded. Lymphomas were classified as aggressive versus indolent based on their histology. Results: There were 36,260 colon cancers diagnosed in 1995-2008 of which 109 (0.3%) were primary non-Hodgkin colon lymphomas. The median age of diagnosis was 67 years. 55 pts had aggressive disease, 27 pts had indolent disease, and 27 pts had inadequate histological data. Diffuse large B cell lymphoma (73%) was the most common aggressive lymphoma whereas it was marginal zone (56%) in the indolent group. The indolent group had 5- year survival rate of 76.9% compared to 48.6% for the aggressive group. Both groups had received different treatment regimens as seen in the Table with variable mean survival outcomes. Conclusions: Our data suggests addition of postoperative adjuvant chemotherapy appears superior to surgery alone in the treatment of aggressive disease whereas it does not appear to provide any benefit in the treatment of indolent disease. However, patient numbers are too small to draw definite conclusions and warrant future investigation in multinational randomized fashion. [Table: see text] No significant financial relationships to disclose.

The hematopoietic cell transplantation-comorbidity index (HCT-CI) has been proposed as a means to estimate the risk of transplant-related mortality (TRM) and the likelihood of overall survival (OS) after allogeneic HSCT. However, its value and applicability remain unclear; in a 2-center study, it was predictive of outcome at one but not at the other in multivariate analysis (Blood2007;110:4606). We investigated the effect of HCT-CI in 130 adult patients with hematologic malignancies undergoing reduced-intensity HSCT after 100 mg/m2 melphalan (+ 50 mg/kg cyclophosphamide if no prior autograft). GVHD prophylaxis comprised cyclosporine/tacrolimus and MMF. 18% of the donor-patient pairs were 1 antigen/allele-mismatched. 57% had refractory disease. 45% had failed an autograft. ECOG performance status (PS) was 0–34%, 1–48%, 2–14%, and 3–4%. The HCT-CI score distribution was 0–10%, 1–4%, 2–28%, 3–24%, 4–15%, 5–10%, 6–8%, and ≥7–2%. Overall, the patient population had higher HCT-CI scores than described in other studies (Cancer2008;112:1992). In multivariate analysis, TRM was higher with HLA mismatch and PS 2-3, and OS was lower with PS 2-3, HLA mismatch, refractory disease, donor age >45 y, elevated LDH, and platelets HCT-CI 0 vs 1-2 vs ≥3 had no effect on TRM or OS. HCT-CI 0-2 vs ≥3 had a borderline effect on TRM (P=0.09) and OS (P=0.15) in univariate analysis, but no effect in multivariate analysis when forced into the model with factors known to be significant. No significant correlation was seen between HCT-CI and any of the factors found to be predictive of outcome. Figure Figure Because serum albumin is a powerful non-specific predictor of general health and outcome in all clinical situations, we hypothesized that it would correlate with the PS. As shown in the figure below, it did. We expected that it would correlate with HCT-CI because increasing comorbidity should theoretically be associated with declining albumin. However, it did not. Figure Figure In our experience, HCT-CI does not correlate with outcome – especially when other pertinent factors are taken into account. Since most data supporting HCT-CI have originated from a single center, it is possible that its applicability depends on individual centers and the treatment protocols employed. However, lack of correlation of HCT-CI with albumin does call its biological plausibility into some question. HCT-CI cannot be employed unless refined and validated prospectively in multi-center studies.

Although allogeneic HSCT is potentially curative in myeloma, series reporting encouraging results with submyeloablative regimens suffer from limited follow-up and incomplete information on prognostic factors known to be relevant in myeloma. The outcome of 24 myeloma patients (50–66 years, median 52) undergoing reduced-intensity allogeneic HSCT after 100 mg/m2 melphalan from related (n=21) or unrelated (n=3) donors. The 9 patients who had not relapsed after preceding autotransplantation received 50 mg/kg cyclophosphamide in addition. No patient underwent a planned sequential autograft-allograft procedure. Complete prognostic factor information was available on each patient. High-risk disease (n=16) was defined by one or more of the following: del(13) on conventional karyotyping, t(4;14), del(17p), plasma cell labeling index >1%, elevated LDH, plasmablastic morphology. The disease was refractory to therapy in 16 patients. Three patients (13%) had disease that was neither high-risk nor progressive, 10 had disease that was either high-risk or refractory, and 11 had refractory, high-risk disease. Four patients died of toxicity (3 GVHD, 1 multiorgan failure) and 19 relapsed. 18 of 19 relapsing patients died of progressive disease and 1 is alive in CR after a second allograft. High-risk (RR 0.11, P=0.0007) disease and refractoriness to therapy (RR=0.10, P=0.0006) were associated with poorer event-free survival. High-risk (RR 0.16, P=0.002) disease and refractoriness to therapy (RR=0.23, P=0.007) were associated with poorer event-free survival. The combination of the two factors resulted in the identification of 3 categories of patients with highly disparate outcomes as shown in Figure 2. Figure 1 shows the effect of the biological nature of the disease on EFS and OS. Figure 1. shows the effect of the biological nature of the disease on EFS and OS. Figure Figure Our data suggest that the outcome of allogeneic HSCT in myeloma is disappointing unless the disease is sensitive to therapy and biologically low-risk. However, such disease responds exceedingly well to autotransplantation–and is associated with prolonged survival that can rival that seen after allogeneic HSCT. Alternative strategies are needed to improve the outcome of patients with refractory or high-risk disease–and may include elective post-allograft maintenance therapy with novel agents such as thalidomide, lenalidomide or bortezomib.

130 patients who were unsuitable for conventional-intensity conditioning underwent RI-HSCT after 100 mg/m2 melphalan (+ 50 mg/kg cyclophosphamide if no prior autograft). GVHD prophylaxis comprised cyclosporine (HLA-matched siblings) or tacrolimus (all others) and MMF. Table 1: Patient characteristics Age (y) 19–71 (median 55) Male 55% Refractory disease 57% ECOG performance status 0 34% 1 48% 2 14% 3 4% Diagnosis Lymphoma 42% Leukemia 36% Myeloma 22% Donor Matched sibling 49% Mismatched sibling 2% Matched unrelated 33% Mismatched unrelated 15% Donor age (y) 21–71 (median 44; 45% >45) Male donor 65% Prior autograft 45% Refractory disease, HLA mismatch, donor age >45, elevated creatinine, low DLCO, thrombocytopenia, male donor, poor performance status, and low albumin affected OS adversely in univariate analysis. The following factors affected outcome independently: Table 2: Cox analysis Adverse variable Relative risk P TRM HLA mismatch 4.78 0.0003 Performance status 2–3 3.07 0.044 Relapse Donor age >45 y 2.0 0.012 Male donor 1.98 0.026 Refractory disease 1.84 0.05 EFS Performance status 2–3 0.48 0.022 HLA mismatch 0.53 0.023 Refractory disease 0.55 0.016 Male donor 0.61 0.039 Donor age >45 y 0.63 0.034 OS Performance status 2–3 0.44 0.025 HLA mismatch 0.31 0.0001 Refractory disease 0.49 0.007 Donor age >45 y 0.55 0.012 High LDH 0.53 0.007 Platelets These prognostic factors were similar to those found on studying the first 63 patients in this series (Mehta et al. Bone Marrow Transplant 2006) –with the additional emergence of HLA mismatch and thrombocytopenia which were significant in univariate but not multivariate analysis then. These data suggest that RI-HSCT is useful for some patients with hematologic malignancies who are ineligible for conventional-intensity HSCT. However, alternative HSCT techniques or non-HSCT options are needed for high-risk patients. Figure 1 shows the effect of the number of adverse prognostic factors on the cumulative incidence of relapse and transplant-related mortality. Figure 1. shows the effect of the number of adverse prognostic factors on the cumulative incidence of relapse and transplant-related mortality. Figure 2 shows the effect of the number of adverse prognostic factors on survival. Figure 2. shows the effect of the number of adverse prognostic factors on survival.

During treatment, patients with myeloma can develop restricted bands in the serum or urine that are different from the original M protein on serum (SIFE) and urine (UIFE) immunofixation electrophoresis. These so-called oligoclonal bands represent transient aberrant recovery of the immune system, and are not associated with any adverse implications. Unless SIFE/UIFE are checked and the bands identified as oligoclonal, a mistaken diagnosis of persistent or recurrent disease may be made. It is not known if the pattern of serum free light chain (SFLC) levels helps differentiate between oligoclonal bands and persistent/recurrent M protein. Data on 219 myeloma patients with serial follow-up were evaluated to identify 3537 encounters which fulfilled the following criteria: available SFLC levels, and 1 or more restricted bands identified on SIFE or UIFE. Patients with non-secretory and biclonal disease were excluded. If a heavy or light chain not part of the original M protein was seen, the presence of an oligoclonal band was diagnosed. If the original M protein was identified intact (e.g. the detection of IgG kappa in a patient with IgG kappa myeloma) or its constituent heavy or light chain were identified in an unbound fashion (e.g. the detection of free IgG or free kappa in a patient with IgG kappa myeloma), the original M protein was felt to be present. Results with oligoclonal bands were further characterized by the additional presence or absence of the original M protein. Only the original M protein was seen in 2661 (75%), 352 (10%) had oligoclonal bands without the original M protein, and an oligoclonal band was seen with the original M protein in 524 (15%). The SFLC ratio was normal (0.26–1.65) in 1306 (37%) and abnormal in 2231 (63%). The relationship of the nature of the restricted bands seen with the SFLC ratio was assessed in two ways in preliminary analysis. In the first, the SFLC ratio was classified as normal or abnormal. In the second, abnormal ratios were classified further as concordant (1.65 for kappa disease) or discordant (1.65 for lambda disease). Discordant ratios were grouped with normal because they did not reflect an excess of the abnormal light chain associated with the original M protein. The following table shows the relationship between the nature of the restricted bands and the SFLC ratio: SFLC ratio SFLC ratio Restricted band category Normal Abnormal Normal or discordant abnormal Concordant abnormal Original M protein only 843 (32%) 1818(68%) 919 (35%) 1742 (65%) Oligoclonal band(s) only 185 (53%) 167(47%) 215 (61%) 137 (39%) Oligoclonal band(s) with original M protein 278 (53%) 246 (47%) 302 (58%) 222 (42%) P As the table shows, the SFLC ratio was normal significantly more frequently when oligoclonal bands were present. This appeared to be unaffected by the presence of bands resembling the original M protein. As the SFLC ratio can be affected by treatment-induced suppression of the uninvolved free light chain, the data were also analyzed as follows: concordant abnormal SFLC ratio with elevated involved free light chain (1890; 53%) versus the rest (1647; 47%). Finally, based on the hypothesis that elevated uninvolved free light chain levels are less likely to be seen with active disease, readings with elevated uninvolved free light chains were transferred from the former category into the latter. The following table shows the relationship between the nature of the restricted bands and the above categories: SFLC ratio SFLC ratio Restricted band category Normal (All others) Abnormal (Concordant abnormal with elevated involved free light chain) Normal (All others) Abnormal (Concordant abnormal with elevated involved free light chain; excluding elevated uninvolved free light chain) Original M protein only 1246 (47%) 1415 (53%) 1299 (49%) 1362 (51%) Oligoclonal band(s) only 247 (70%) 105 (30%) 257 (73%) 95 (27%) Oligoclonal band(s) with original M protein 343 (65%) 181 (35%) 361 (69%) 163 (31%) P Once again, as the table shows, the SFLC ratio was normal (or equivalent of normal) significantly more often when oligoclonal bands were present. We conclude that the SFLC ratio is significantly more likely to be normal when oligoclonal bands are present in patients with myeloma. However, the differences between patients with and without oligoclonal bands are not definitive enough to predict the nature of the bands seen. SIFE and UIFE remain the only definitive means of identifying the nature of the restricted bands seen in patients with myeloma on therapy.

Cytomegalovirus (CMV), an important cause of mortality after allogeneic HSCT in the past, is now controllable with sensitive monitoring techniques and drugs such as valganciclovir and foscarnet. However, some groups still report that CMV seropositivity influences the outcome adversely. The outcome of 130 reduced-intensity allograft recipients treated uniformly (2001–7) was studied to determine the effect of CMV. Table 1: Patient characteristics Age (y) 19–71 (median 55) Male 55% Refractory disease 57% ECOG performance status 0 34% 1 48% 2 14% 3 4% Diagnosis Lymphoma 42% Leukemia 36% Myeloma 22% Donor Matched sibling 49% Mismatched sibling 2% Matched unrelated 33% Mismatched unrelated 15% Donor age (y) 21–71 (median 44) Male donor 65% CMV IgG-seropositive Patient 59% Donor 32% CMV serostatus P+D+ 21% P+D− 38% P−D+ 11% P−D− 30% Prior autograft 45% Table 2: CMV prophylaxis, monitoring and therapy employed Prophylaxis (patient and/or donor CMV-seropositive): - Valacyclovir 500 mg TID from the start of the conditioning regimen ○ Tapered to BID after 100–120 days and to QD at 5–6 months ○ Stopped one month after stopping all immunosuppression - No regular IVIG infusion Monitoring (all patients): - CMV quantitative PCR (previously antigenemia) at each visit ○ Once a week for at least 2 months ○ Subsequently, every 2–4 weeks Therapy: production - Viremia ○ Valganciclovir 900 mg BID (previously ganciclovir 5 mg/kg BID IV) for 1 week (1 more week if viremia persistent) and then 900 mg QD (ganciclovir 5 mg/kg QD IV) for 2 weeks; adjusted for kidney function ○ Foscarnet 100 mg/kg for persistent viremia or ANC CMV reactivation was seen in 40 patients, and was influenced by serostatus (12 P+D+, 26 P+D−, 1 P−D+, 1 P−D−; P Figure 1: The effect of patient and donor cytomegalovirus serostatus on TRM (P=0.58) and relapse (P=0.97) Figure 1:. The effect of patient and donor cytomegalovirus serostatus on TRM (P=0.58) and relapse (P=0.97) Figure 2: The effect of patient and donor cytomegalovirus serostatus on overall survival (P=0.67) Figure 2:. The effect of patient and donor cytomegalovirus serostatus on overall survival (P=0.67) Outcome was influenced by factors described previously in a subgroup of these patients (Mehta et al. Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant2006; 38:95–100). We conclude that intensive monitoring for CMV reactivation, effective anti-viral drugs, and intensive supportive therapy have eliminated the adverse influence of CMV-positivity on the outcome of allogeneic HSCT.

CD34+ cell dose calculations for hematopoietic stem cell transplantation (HSCT) are usually based on actual body weight (ABW). We have shown that ideal body weight (IBW) provides a better basis for this in a small population of patients with hematologic malignancies (Ali et al. Bone Marrow Transplant2003;31:861–4). However, a concern has been raised that this may not be applicable in myeloma because of underestimation of IBW as a result of disease-related height loss (Maclean et al. Bone Marrow Transplant2007;40:665–9). We studied this relationship further in 514 myeloma autografts conditioned with 140 or 200 mg/m2 melphalan. The CD34+ cell doses (106/kg) by IBW and ABW were 1.37–39.36 (median 6.03) and 1.15–29.67 (median 4.84) respectively. The difference between ABW and IBW was −25 to +124% (median +26%). The analysis was performed for the entire group as well as after excluding outliers (engraftment before 8 or after 16 days). As Table 1 shows, IBW-based cell doses correlated better with engraftment than ABW-based (higher r2 and F): Table 1: Correlation between the CD34+ cell dose by IBW or ABW and various engraftment endpoints IBW ABW Engraftment endpoint(109/L) r2 F P r2 F P All patients Neutrophils 0.5 0.83 2453 As Table 2 shows, CD34+ cell doses based on IBW as well as ABW significantly affected engraftment when analyzed separately as continuous variables. However, when analyzed together, only the dose based upon IBW retained significance: IBW ABW Engraftment endpoint (109/L) Univariate Multivariate Univariate Multivariate All patients ANC 0.5 1.0471 (P Table 2: Relationship between engraftment and the CD34+ cell dose analyzed as a continuous variable (risk ratio and P value) This observation is important in practice to avoid subjecting a patient to additional mobilization and apheresis procedures if the target cell dose has been met based on IBW. With increasing obesity (half the patients were >25% overweight), accounting for the correct weight is an important practical consideration. Infusion of an appropriate number of cells also allows for extra cells to be retained for possible future use. In this group, if every patient’s height was underestimated by 1 inch (i.e. was increased by 1 inch for the purpose of calculations – assuming an element of kyphosis), IBW of men would have increased by 2.4–6.0% (median 3.2%) and IBW of women by 9.3–17.6% (median 12.4%). This suggests that implications of a height difference for calculating IBW in men are minimal but could be significant in women. We conclude that a CD34+ cell dose based on IBW is a better predictor of engraftment speed than one based on ABW, and IBW should be used as the basis for cell dose calculations in autologous HSCT. Any height loss, especially in myeloma patients, should be taken into account while calculating IBW for this purpose.

Whether the CD34+ cell dose affects the outcome of allogeneic blood cell transplantation is contentious: it is generally accepted that low doses increase transplant-related mortality (TRM) but it is unknown if very high doses compromise outcome by increasing GVHD. The aim of this analysis was to see if an optimum CD34+ cell dose (106/kg ideal body weight) could be found among 130 patients undergoing reduced-intensity allografts after 100 mg/m2 melphalan (+ 50 mg/kg cyclophosphamide if no prior autograft). GVHD prophylaxis comprised cyclosporine/tacrolimus and MMF. Among patients receiving CD34+ cell doses of 8 (n=6), the overall survival (OS) of the last group was the worst. Using the likelihood-ratio statistic for proportional-hazards regression models, the outcome of the first 4 groups was found to be not significantly different (P>0.05) from the last whereas those receiving 6–6.99 (RR 0.23; P=0.003) and 7–8 (RR 0.25; P=0.004) fared better. Amongst the 124 patients receiving ≤8/kg, an increasing cell dose was associated with improving OS when analyzed as a continuous variable (RR 0.8759; 95% CI: 0.7695–0.9970; P=0.045), and the OS of those receiving 6–8/kg was better than those getting Figure Figure When the CD34+ cell dose was entered into a Cox model (6–8 vs the rest) with the 6 other variables found to be independently significant in this population of patients (performance status 2–3, HLA mismatch, refractory disease, donor age >45 y, high LDH, and platelets 8), 6–8 was better (RR 0.33 vs >8; P=0.029, and RR 0.63 vs The 6–8 cell dose was associated with lower relapse (RR 0.72; P=0.19) and TRM (RR 0.61; P=0.19) when analyzed with other variables significantly affecting these outcomes; suggesting that its beneficial effect on OS may be a combination of improved relapse and TRM. There was no significant correlation between the cell dose and some donor characteristics (sibling/unrelated, gender, and HLA match). Donor age ≤45 was associated with a cell dose of 6–8 (55% vs 34% for >45 y; P=0.02). We conclude that the CD34+ cell dose affects outcome of reduced-intensity allogeneic HSCT. This finding is important because this is the only potentially modifiable factor that can be manipulated in practice. Based on our data and pending more studies, we recommend 6–8 x 106 per kg ideal body weight to optimize outcome.

It is thought that 2 x 106/kg is the minimum CD34+ cell dose needed for autotransplantation, while the ideal dose is generally accepted to be 5 x 106/kg. Whether infusing cell doses higher than 5 x 106/kg offers additional benefit is unknown. The relationship between time to standard engraftment endpoints (0.5 x 109/L Neutrophils – ANC 0.5, 1 x 109/L neutrophils – ANC 1.0, 20 x 109/L platelets – PLT 20, and 50 x 109/L platelets – PLT 50) and the CD34+ cell doses infused was explored in 754 autografts performed for malignant diseases in adult patients: 32 leukemia, 195 lymphoma, 514 myeloma, 13 other. The conditioning regimens used were standard (high-dose melphalan, BEAM, busulfan-cyclophosphamide, or busulfan-etoposide in >90%). All patients received G-CSF after stem cell infusion: from day 0 in 90%. Cell dose calculations were based upon ideal body weight. Table 1 shows the distribution of the CD34+ cell ranges infused. Table 1: CD34+ cell numbers infused (10 6 /kg IBW) CD34+ cell dose n CD34+ cell dose n ≤3 42 >3 712 ≤4 109 >4 645 ≤5 260 >5 494 ≤6 434 >6 320 ≤7 534 >7 220 ≤8 586 >8 168 ≤9 619 >9 135 ≤10 646 >10 108 ≤15 714 >15 40 Figure 1 shows the mean days to achieving the 4 engraftment endpoints under study by the number of CD34+ cells infused. It is clear that increasing CD34+ cell doses hasten platelet recovery significantly through the entire range of CD34+ cell dose ranges studied. Increasing CD34+ cell doses appear to hasten neutrophil recovery too, but the benefit seems to level off beyond 10 x 106 CD34+ cells per kg. The effect of a CD34+ cell dose of ≤2 x 106/kg was not analyzed because only 7 patients received this small quantity of cells. Figure 1: The effect of different CD34+ cell dose ranges on various engraftment endpoints Figure 1: . The effect of different CD34+ cell dose ranges on various engraftment endpoints The relationship between CD34+ cell doses and engraftment holds true even when the data are analyzed in a dichotomous fashion as shown in Figure 2. Figure 2: Differences in engraftment based upon CD34+ cell doses Figure 2: . Differences in engraftment based upon CD34+ cell doses CD34+ cell dose bands ANC 0.5 ANC 1.0 PLT 20 PLT 50 ≤3/>3 0.28 0.003 0.083 0.43 ≤4/>4 0.029 0.0007 0.027 0.39 ≤5/>5 0.002 0.001 0.0004 0.031 ≤6/>6 7 8 9 10 15 0.005 0.001 0.003 0.004 Table 2 shows the significance of the differences illustrated in Figure 2. Table 2: Significance of differences in time to engraftment These data suggest that increasing CD34+ cell numbers hasten hematologic recovery – even beyond a cell dose of 15 x 106/kg. It remains to be seen if more rapid engraftment resulting from infusion of higher number of CD34+ cells results in practical benefits such as more robust/durable engraftment, decreased toxicity, and improved survival.