Litzow, Mark R.

Abstract Background The timing of SCT for treatment of AML after first relapse is controversial, i.e.,whether to proceed to SCT at the time of relapse or to proceed to chemotherapy re-induction first in an attempt to reach a second remission. The purpose of this study is to determine the optimal time of allogeneic SCT in AML patients in first relapse by comparing outcomes of allogeneic SCT between patients untreated and patients post re-induction chemotherapy. Method This retrospective study was approved by the Mayo Foundation IRB. Between February 1983 and March 2003, 60 patients with AML in untreated first relapse (REL1) or post re-induction chemotherapy (CT) underwent allogeneic SCT in Mayo Clinic, Rochester. Study outcome included overall survival (OS), disease free survival (DFS), and transplant related mortality (TRM). The outcome was compared between the patients who underwent allogeneic SCT at REL1 and CT. Survival was analyzed using Kaplan-Meier (KM) and groups were compared statistically with the log-rank test. Result Of the 60 patients receiving allogeneic SCT , 25 patients and 35 patients underwent SCT at REL1 and CT, respectively. In the group of CT, 23 patients (66%) achieved CR2 while 12 patients (34%) had refractory disease. Forty-nine of 60 patients received cyclophosphamide and total body irradiation (Cy/TBI) as a conditioning regimen and the remainder received busulfan and cyclophosphamide( Bu/Cy). Patients in REL1 were older at SCT (median age 38 vs 31 years p= 0.024 ) and had lower percentage blast cells in bone marrow at first relapse (median 15% vs 50% p=0.00095) than in CT group. Difference in other baseline characteristics were not significant. KM analysis showed that the two groups did not show statistically differences in OS (p=0.43), DFS (p=0.68), and TRM (p=0.25). However, there were trends toward longer median OS (26.2 vs 5.4 months) and DFS (11.9 vs 3.3 months) with REL1 versus CT. OS at 1 year was 56 % for REL1 and 34.3 % for CT and at 5 year 32.1 % and 28.6 %, respectively. DFS at 1 year was 48 % for REL1 and 31.4 % for CT and at 5 years 22.9 % and 24.5 % respectively. TRM at 1 year was 25% for REL1 and 40 % for CT. A univariate Cox Proportional Hazard analysis for survival showed that unfavorable cytogenetics at diagnosis and relapse, antecedent MDS, and shorter duration of CR1 were significantly associated with a higher risk of death. Higher percentage of blast cells in bone marrow at first relapse was not significantly associated with a higher risk of death. In a multivariate model, unfavorable cytogenetics at first relapse and shorter duration of CR1 were both significantly associated with an increased risk of death. In this study, even after adjusting for other factors in a multivariate model, the difference between REL1 and CT groups was not statistically significant. Conclusion This study suggests that outcome of allogeneic SCT was comparable between REL1 and CT. Patients with AML in first relapse may proceed to allogeneic SCT because there appear to be no statistical differences in REL1 versus re-induction chemotherapy before SCT. REL1 patients tended to have a better outcome than CT patients.

Abstract Abstract 4228 Background Peripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy, mobilization strategy, underlying disease, among others. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization is reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating factor) + GM-CSF (Granulocyte–Macrophage Colony-Stimulating factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. Methods We studied 656 first time, G-CSF based PBSC mobilizers with Non-Hodgkin Lymphoma (562; 86%), or Hodgkin's Disease (94; 14%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (Receiver operating characteristic) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 5 million/kg as the ideal collection for the current analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. Results We first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9/uL. Among those with ≥9/uL, only 6.6 % failed to collect at least 2 million compared to 55% among the rest (P < 0.001). These numbers were 6.3% and 50% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 9.1/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >=9.1/uL, only 22% failed to collect at least 2 million compared to 79% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 49% achieved a count of 9.1/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 9.1 on day 2 and found this to be 5.2/uL. Among those with day 1 pCD34 ≥ 5.2/uL, 79% reached day 2 pCD34 ≥ 9.1 compared to 24% among the rest (P < 0.001). We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs for a target of 5 million/kg for one transplant. The best day 1 or day 2 pCD34 predicting a 5 million/kg yield in 5 collections was 17/uL. Among those with day 1or 2 pCD34 ≥ 17/uL, 4% failed to reach 5 million in ≤ 5 days compared to 96% among the rest (P < 0.001). Conclusions This study provides an estimate of optimal pCD34 count thresholds for early identification of patients with lymphoma at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and these patients appear to have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as addition of plerixafor can be considered if pCD34 count is < 6/uL on day 1 or < 10/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation based on the current study would be 17/uL for a target of 5 million. Such a target-adapted strategy may be more appropriate. Disclosures: Kumar: Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding. Gertz:Genzyme: Research Funding. Micallef:Genzyme: Research Funding.

Abstract Abstract 4152 BACKGROUND: Patients with biologically aggressive chronic lymphocytic leukemia (CLL) characterized by being refractory to purine nucleoside analogues and/or possessing the cytogenetic abnormality del (17p13) have poor clinical outcomes with a median survival of <3 years. Several groups have reported that nonmyeloablative allogeneic stem cell transplant (alloSCT) provides long-term disease control in a subset of high-risk CLL patients. The Seattle group also recently reported that alemtuzumab use prior to alloSCT may increase the risk of early relapse/progression (Sorror, ASH 2010). This is a potentially critical observation since alemtuzumab is one of the few active agents in patients with del(17p13) and is frequently used for pre-transplant debulking in patients with this genetic defect. METHODS: We performed retrospective analysis of 38 CLL patients who underwent nonmyeloablative alloSCT for CLL at the Mayo Clinic between 2003 and 2011. The relationship between transplant outcome and debulking regimen used immediately prior to alloSCT, disease status at the time of alloSCT, post transplant engraftment, GVHD development was explored. The degree of marrow involvement prior to alloSCT was assessed using the leukemia index calculated by multiplying the % involvement by CLL cells and the % cellularity. RESULTS: Median age at the time of alloSCT was 55.5 (range, 29–69) and 13 patients (34%) were female. The median duration from CLL diagnosis to alloSCT was 4.7 years. Thirty-two patients (84%) had received more than 3 prior therapies prior to alloSCT. Thirty-seven patients (97%) had received purine analog-based therapies, 18 (47%) patients had received alkylating agents and 25 (66%) had received alemtuzumab. 33 (87%) patients were purine analog refractory. On cytogenetic evaluation by FISH, 17 (45%) patients had del(17p13), 10 (26%) had del(11q23) and 1 (3%) had del(6q23). Nine patients were in complete remission (CR) by IWCLL 2008 criteria at the time of alloSCT and 7 patients were in complete remission with incomplete marrow recovery (CRi). Of the remaining 22 patients, 20 had either a partial remission or stable disease at the time of alloSCT and 2 had progressive disease. Two (5%) patients had bulky lymphadenopathy (≥ 5cm by CT imaging), 11 (29%) patients had splenomegaly, and 8 (21%) patients had more than 30% CLL involvement by the leukemia index. Fludarabine (F) and 200cGy total body irradiation (TBI) was used as the conditioning regimen for 35 patients (92%). 22 patients received unrelated donor grafts (15 matched, 7 mismatched), and 16 received related donor grafts (all matched). Patients received mycophenolate (MMF) and either tacrolimus (unrelated grafts) or cyclosporin (related grafts) for graft versus host disease (GVHD) prophylaxis. 31 out of 37 evaluable patients (84%) achieved initial 100% donor chimerism (22 within 100 days) and 24 (63%) developed ≥grade 2 GVHD. After median follow-up of 1 year (range = 0–5.4 years), 26 of 38 patients (68%) are alive, and the median overall survival is 47 months. To date, 13 (34%) have experienced CLL progression/relapse requiring accelerated taper of GVHD prophylaxis (n = 2), donor lymphocyte infusion (n = 5), or chemo/immunotherapies (n= 6). For the 12 deceased patients, causes of death was CLL relapse/progression (n = 5), GVHD (n = 2) and infectious or other complications without CLL relapse/progression (n = 5). Pre-transplant use of alemtuzumab (A) within 3 months of transplant was the only pre-transplant characteristics associated with overall survival (OS). Median OS of patients receiving A within 3 months of alloSCT was 1 year compared to not reached for those who did not receive A within 3 months of alloSCT (p = 0.011; Figure 1a). A trend was also observed between alemtuzumab use within 12 months of alloSCT; however, it did not reach statistical significance (p=0.069; Figure 1b). No statistically significant associations between residual marrow involvement at time of alloSCT (p = 0.93), type of graft (p = 0.65), or presence of del (17p13) (p = 0.13), number of prior treatments (p = 0.45), patient age (p = 0.80) or disease status at time of alloSCT (p = 0.21) were observed. CONCLUSION: In this cohort of patients with high risk CLL, alemtuzumab use prior to transplant was the greatest predictor of OS after nonmyeloablative alloSCT. Non-alemtuzumab based debulking strategies need to be developed for patients with del (17p13). Disclosures: No relevant conflicts of interest to declare.

Abstract Few data are available on the outcomes of patients who fail to engraft following URD transplantation. We describe the results of 122 patients reported to the National Marrow Donor Program (NMDP) between 1990 and 2005, who received a second bone marrow (BM) or peripheral blood (PB) URD transplant after failing to achieve an absolute neutrophil count of ≥ 500/mm3 without evidence of recurrent disease. Patients were transplanted for leukemia (n=83), myelodysplastic disorders (n=16), severe aplastic anemia (n=20) and other disease (n=3). The median age at first transplant was 29 years. Approximately one third were in each age range, < 20 (33%), 20–40 (37%) and >40 (29%). The initial transplant was BM in 84% of patients while 51% received BM for the subsequent transplant. One hundred ten of these patients received two transplants, 11 received three and one received 4 transplants. Twenty four used a different donor whereas 98 used the original donor for the second transplant; 28 of these used cells that had been cryopreserved at the initial transplant date. Nearly two thirds of the patients received reduced intensity conditioning or no conditioning for the second transplant. Sixty one percent had ATG as a component of their second transplant. The median interval from first transplant to second transplant was 48 (range, 18–126) days. The median nucleated cell dose was 2 × 108/kg (range, <1–23) for the first transplant and 2 × 108/kg (range, <1–50) for the second. The median follow up of survivors after second transplant was 77 (range, 2–144) months. Univariate probabilities of outcomes for these patients after second transplant were: Outcome N eval Probability (95% CI) *cumulative incidence Neutrophil engraftment* 122 @ 28 days 43 (34–52) % @100 days 48 (39–57) % 30 day mortality 122 39 (31–48) % 100 day mortality 122 75 (67–82) % Overall survival (OS) @ 1 year 122 11 (6–17) % Treatment related mortality (TRM) @ 1 year* 99 86 (79–92) % Disease free survival (DFS) @ 1 year 99 7 (2–12) % Of the 122 patients analyzed, only 10 remain alive. The most common causes of death were graft failure or rejection (33%), organ failure/interstitial pnuemoniatis (22%), infection (15%), GVHD (14%) and recurrent disease (6%). Of the 37 patients who had persistent graft failure 21 (57%) died from infectious causes. We observed no differences between patients who received a graft from the same donor vs. different donor, fresh vs. cryopreserved cells, or small initial graft size vs. large initial graft size. Patients who received a T-cell depleted graft at the time of their first transplant had significantly worse survival at 1 year after their second transplant, 4% (95% CI, 0–11) compared to those patients who had a non T-cell depleted initial graft, 16% (95 % CI, 8–25)(P = 0.02). It appears that a second salvage transplant strategy may be effective in a small group of patients, although the overall DFS at 1 year of only 7% is disappointing. To improve these results, efforts might focus on early identification and treatment of those at highest risk for non engraftment to determine whether such a strategy can alter the natural history we have described.

Abstract Peripheral blood infused total autograft absolute lymphocyte count (A-ALC) correlates with day 15 absolute lymphocyte count and is an independent prognostic factor for survival after autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Factors to enhance A-ALC collections are not well defined. We hypothesize that the number of peripheral blood apheresis collections (PBAC) directly correlates with A-ALC. 190 consecutive NHL patients who underwent ASCT at the Mayo Clinic between 1993 and 2001 were analyzed. The primary end point of the study was to assess the correlation between the number of PBAC and A-ALC. The secondary end point was to determine if the number of PBAC affected survival post-ASCT. Of the 190 patients, 18 patients underwent 1 PBAC, 23 patients 2 PBAC, 50 patients 3 PBAC, 37 patients 4 PBAC, 50 patients 5 PBAC, and 12 patients had ≥ 6 PBAC. There was no association between the number of PBAC and the number of CD34+ stem cells collected (p= 0.25). A strong association between number of PBAC and A-ALC (Kruskall Wallis test, p <0.0001)(Figure 1) was identified. Using a cut-off of 4 PBAC, superior overall survival (OS) and progression-free survival (PFS) were observed for patients that underwent 4 PBAC or more compared to patients that underwent less than 4 PBAC (86 months vs 18 months, p <0.0001; 76 months vs 10 months, p <0.0001, respectively). Multivariate analysis demonstrated PBAC ≥ 4 is an independent prognostic factor for OS (RR = 0.654, 95%CI: 0.529–0.804, p< 0.0001) and for PFS (RR = 0.682, 95%CI: 0.561–0.826, p< 0.0001) when compared with other significant factors including performance status, lactate dehydrogenase and extra nodal disease. These data suggest that increasing the number of PBAC beyond the minimum number required to meet CD34+ collection targets may result in improved overall and progression-free survival mediated by an increase in autograft absolute lymphocyte count.

Background: Primary amyloidosis (AL) is characterized by multi-organ deposition of light chain derived amyloid protein, resulting in organ dysfunction of varying severity. High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective treatment for AL, but is limited in applicability due to high transplant related mortality in patients with advanced organ dysfunction. Serum LDH, an enzyme that catalyzes the conversion of lactate to pyruvate, is present in large amounts in heart, kidney, liver, and muscle and is elevated with abnormalities in one or more of the organs. It is commonly elevated in a variety of hematologic malignancies. Given the multi-organ involvement in AL, we examined the prognostic value of LDH in AL. Methods: We examined our transplant database to assess the prognostic value of LDH. Laboratory values from pre-ASCT evaluation were used for the analysis. Results: Three hundred and thirteen pts who underwent ASCT between March 1997 and March 2007 were included in this analysis. The median age at ASCT was 57.5 years (range, 33–73); and 183 pts (58.3%) were male. The median duration from diagnosis to transplant was 4.1 months (range, 1–75) and the median follow up post transplant was 28.3 months (range, 1 m to 10 years) for the 229 pts (73%) alive at the time of analysis. The median LDH was 194 IU (range, 92-441) and 138 pts (44%) had an LDH > 200. The median overall survival post-ASCT for patients with an LDH > 200 was 59.4 mos (95% CI; 37.9, 80.8) compared to not reached for the rest (Figure). The prognostic value of LDH for post transplant OS was independent of cardiac troponin (cTnT). The median OS post ASCT for patients with cTnT > 0.035 (n=208) was 37.4 months (95% CI; 17, 57.9) compared to 97.5 months (95% CI; 64.8, 130.2) for the rest. In a Cox proportional hazards model, cTnT > 0.035 was associated with a 2.5 fold risk of death (p = 0.0013) and an LDH > 200 was associated with 1.7 fold risk (p = 0.04). We then examined if LDH added to the cTnT in a prognostic model for survival post ASCT. Pts with both cTnT < 0.035 and LDH < 200 (n=133) had a median OS that was not reached compared to 71 mos (95% CI; 48.3, 94) if one factor was abnormal (n=89) and 37.4 mos (95% CI; 16.1, 58.8) if both cTnT and LDH were abnormal as above (n=45); p < 0.001 (Figure 2). Conclusions: In this study we have demonstrated the prognostic value of serum LDH in AL pts undergoing ASCT. Serum LDH appears to add to the value of troponin in prognostic staging of these patients. These results need to be examined in a larger cohort of patients undergoing different treatments. It is possible that LDH is able to globally assess abnormalities of multiple organs including heart, liver and lung. Prospective studies looking at the different LDH fractions are ongoing. Figure Figure Figure Figure

Background: High dose chemotherapy and autologous stem cell transplant (SCT) remains the preferred therapy for eligible patients with multiple myeloma (MM). Several studies have demonstrated an improvement in median survival with use of SCT. Patients with myeloma may undergo SCT immediately following 4–6 cycles of ‘induction’ therapy or at the time of relapse from the initial plateau phase. Available evidence does not suggest a survival difference between the two approaches. Methods: We retrospectively evaluated our experience with autologous single SCT for MM to compare the results of delayed SCT to early SCT. We identified from our transplant database, 202 patients with MM, who underwent SCT between October 1992 and November 2002. 101 patients, who responded to induction chemotherapy, had stem cells collected in plateau phase, received maintenance chemotherapy and had SCT at the time of first relapse (delayed SCT group). The remaining 101 patients, after initially achieving a response underwent upfront SCT (early SCT group). Patients refractory to initial therapy were excluded from this study. Most of the early transplants were done in the recent years and hence this group has a shorter follow up. Results: The study cohort had a median age of 55 years (range 29 – 72) at diagnosis consisting of 126 males (62%), with no significant demographic difference between the two groups. As expected measures of tumor burden (M protein, B2M and marrow plasma cell percentage) were significantly higher in the delayed group. Plasma cell labeling indices and presence of abnormal cytogenetics were higher in the delayed SCT group as well at transplant. TBI containing regimens were used more often in the delayed group reflecting a difference in the time periods of transplant. There was no difference between the groups in terms of overall response to transplant though complete response rate was higher for the early transplants. (Table). There was no difference in the time to overall response between the groups (P=0.13, Kaplan Meier estimate). Though the median progression free survival (PFS) from transplant was shorter for the delyaed SCT group, the overall survival (OS) from diagnosis of MM was comparable for the two groups (Table). The overall survival estimate at 5 year from diagnosis was 60% for both groups. Conclusions: Review of our experience demonstrates comparable overall survival for an early SCT compared to SCT at the time of relapse. Although there is an advantage for early SCT in terms of more chemosensitive disease as shown by a longer PFS from SCT, there is no benefit in OS from time of diagnosis. Patient preference and other co-morbidities should play a role in the decision regarding timing of transplant. This study has the disadvantage of being retrospective in nature and the two groups being spread over different periods in time. Early (n=101) Delayed (n=101) P Overall Response 100 (99%) 94 (94%) 0.07 Complete Response 43 (42%) 28 (27%) 0.04 Median PFS (From Transplant) 26.7 months 14.8 months <0.0001 Median OS (From diagnosis) 67 months 70 months 0.1

Abstract Introduction: Mortality rates associated with stem cell transplantation are considerably higher than those of autologous stem cell transplantation for other hematologic malignancies. The efficacy of stem cell transplantation in amyloidosis largely is determined by treatment-related mortality rates (range, 11%-25%). Appropriate patient selection is essential to avoid this high mortality rate. Patients & Methods: The primary end point of the study was death from any cause between 4 days before transplantation and d+100 after transplantation. Patient characteristics are shown. Patient characteristics (N=271) Characteristic Median (range) Comment Age, y 58 (33–75) Male 159 (59%) Renal involvement 184 (68%) Cardiac involvement 147 (54%) Peripheral neuropathy 30 (11%) Hepatic involvement 28 (14%) Albumin, g/dL 2.8 (0.8–4.4) Creatinine, mg/dL 1.1 (0.6–12.0) 90% of patients had levels ≤1.7 mg/dL Alkaline phosphatase, U/L 93 (31–1,395) 25% of patients had levels >132 U/L Urinary total protein, g/d 3.35 (0.01–35.4) Percentage of plasma cells in the marrow 7 (0–78) 90% of patients had <17% plasma cells Interventricular septal thickness, mm 13 (7–25) Ejection fraction, % 65 (28–84) Time between diagnosis and stem cell transplantation, mo. 4 (0.8–75) Troponins,μg/L 0.01 (0.01–1.0) 75% of patients had levels ≤0.03 g/L 90% of patients had levels ≤0.08 g/L Results: Among 271 patients undergoing stem cell transplantation, troponin T was a powerful predictor of treatment-related mortality. Patients with troponin levels of 0.06 mg/L or higher had a day 100 all-cause mortality rate of 28%. Day-100 Survival Rate (N=271) Patients Troponin level ≥0.06 μg/L, no. of patients (n=40) Troponin level <0.06 μg/L, no. of patients (n=231) Total no. of patients *P<.001 Died before day 100* 11 16 27 Survived beyond d+100 29 215 244 Patients with troponin levels less than 0.06 mg/L had a day-100 all-cause mortality rate of 7% (P<.001). Figure Figure Despite possibly having multiple causes of death, for 7 of 11 patients with elevated troponin levels, cardiac causality could be inferred. For patients with low levels of troponin, clear cardiac causality was observed in 4 of 16. Among the 40 patients with troponin levels of 0.06 mg/L or higher, the conditioning dosage of melphalan was reduced for 31 patients (78%). Among the patients with troponin levels less than 0.06 mg/L, the dosage of melphalan was reduced for 29% of patients. Conclusion: Troponin levels should be measured in all patients before transplantation. Those with troponin levels exceeding 0.06 mg/L should be considered for less toxic therapies until the clinically optimal use of stem cell transplantation is better defined by randomized clinical trials. The chemotherapy dosage was reduced for 77% of patients in the high troponin group, but acceptable treatment-related mortality rates were not achieved. Clearly, a risk-adapted approach that modified the dosage of conditioning chemotherapy did not compensate for poor patient health or advanced cardiac involvement.

Abstract Background: Nilotinib, a 2nd-generation BCR-ABL inhibitor, is 20–30 times more potent than imatinib in vitro. A phase II, open-label study of safety/efficacy of nilotinib in pts with imatinib-resistant/intolerant Ph+ CML-CP or -AP was reported. Planned starting dose was 400mg BID, with escalation to 600mg BID if response was inadequate. The objective of the post-hoc analysis was to evaluate safety/efficacy of nilotinib 600mg BID in CML-CP pts who had dose escalation. Methods: Starting dose was 400mg BID. If response was inadequate (failure to achieve complete hematologic response [CHR] by 3 mos, minimal cytogenetic response [CyR] by 6 mos, or major cytogenetic response [MCyR] by 12 mos; loss of HR, CyR, or progression), nilotinib to 600mg BID dosing was permitted. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBC, blasts, basophils, or platelets) or no HR in peripheral blood and/or bone marrow after 4 wks. Results: Of 320 enrolled pts in CP, 269 remained on nilotinib 400mg BID; 51 pts were dose-escalated to 600mg BID for inadequate responses (mean age 57.7 yrs; 68.6% male). All pts met the study criteria for imatinib resistance. Prior imatinib dose was ≥600mg QD in 98% pts and ≥800 mg QD in 53%. 43/51 (84%) pts had no baseline CHR; 38% had no prior history of complete cytogenetic response (CCyR). 35% had prior MCyR. Median time to dose escalation was 169 (114–211) d. 14 (27.5%) pts remain on therapy; median time to discontinuation from study was 307 (235–414) d. 5 pts with disease progression and no deaths were observed among pts who received 600mg BID. CHR was achieved in 58% of evaluable pts without CHR at baseline (n=43). MCyR occurred in 29% of evaluable pts (15/51) on 600mg BID; 10% (5/51) CCyR. Disease progression was low, occurring in 10% (5/51) of pts on 600mg BID. Median time to progression for CP pts on 600mg BID was 12 mos, substantially less than for pts who stayed on 400mg BID (median not observed yet, at least 20 mo). Nonhematologic AEs in 600mg BID pts were similar to those reported for the entire CP cohort from the phase II study. Grade 3/4 hematologic lab abnormalities were: anemia 13.8%, neutropenia 7.9%, thrombocytopenia 13.7%. Hyperglycemia and elevated bilirubin occurred in 6% and 10% of pts, respectively, on 600mg BID. Conclusions: Some HR and CyR after dose escalation to 600mg BID were observed. Safety/tolerability for 600mg BID were similar to the entire CP cohort. Based on these preliminary data, nilotinib dose escalation to 600mg BID in imatinib-resistant Ph+ CML-CP pts may be effective in pts with inadequate responses to 400mg BID. As might be expected in a more resistant population, response duration was shorter than reported for the phase II CP cohort. Additional follow-up is necessary. Use of 600mg BID is not currently recommended for imatinib-resistant CML-CP pts outside clinical studies.

Background: Despite development of new therapies and advances in autologous hematopoietic stem cell transplantation (HSCT), MM remains, for the most part, an incurable condition. Allogeneic HSCT, through induction of a graft-versus-myeloma effect, can potentially overcome resistance to conventional therapy and induce prolonged disease control. Such approach is limited by the risk of acute and chronic GVHD and the high treatment-related mortality and has been restricted to young patients with aggressive or refractory disease. We reviewed our experience with allogeneic HSCT at Mayo Clinic, Rochester, MN. Methods: Retrospective single-institution review of consecutive allogeneic transplants performed for multiple myeloma between 1991 and 2006. Results: Thirty-three patients underwent a myeloablative (52%) or reduced-intensity conditioning (48%) HSCT 3.2 months to 15 years after their diagnosis of multiple myeloma (n=31) or plasma cell leukemia (n=2). Median age at the time of HSCT was 48 years (range 33–61) and 19 patients (57%) had received one (n=12) or two (n=7) prior autologous HSCT. Donors were HLA-matched siblings in 25 cases (76%), matched unrelated (n=8), and 5/6 (n=1) and 6/6 (n=1) match, non-sibling family members. Source of HSC was peripheral blood exclusively in 21 (64%) and bone marrow in 12 (35%) transplants. Outcomes are being reported after a median follow up of 21.8 months (25.6 for survivors). Day+100 mortality was 21.2% and the incidences of any grade and grades 3/4 acute GVHD were 54.5% and 33.3% respectively. Among the 26 patients surviving beyond day+100, 57.7% developed chronic extensive GVHD. All 6 patients transplanted after a complete response (CR) to prior therapy remained so after the transplant. Of the 27 patients with measurable disease, disease reassessment could be performed for 20 after the transplant. Ten patients (50%) achieved a CR or near-CR and 8 patients (40%) obtained a partial response. Median time to progression and overall survival (Figure) after HSCT were 21.8 and 40.6 months respectively. Twenty-one patients have died, 10 as a consequence of disease progression. Twelve patients are alive, including 6 patients in CR, 8.3 to 172.7 months after the transplant. In a multivariate model the use of a non-sibling donor and peripheral blood HSC were associated with decreases risk of relapse, but had no effect on overall survival. Conclusion: Allogeneic HSCT is a feasible treatment for young patient with adverse disease features. Graft-versus-myeloma can induced myeloma eradication and prolonged disease control. Figure Figure