Post ASCT Research Articles

Efficacy of radioimmunotherapy-based conditioning with high-dose chemotherapy and autologous stem cell transplantation for transformed lymphoma.

8556 Background: Transformed non-Hodgkin lymphoma (TF NHL) has a poor prognosis with median survival of 7-20 months. Studies have suggested the benefit of HDC. The series by Eide showed 47%, 5yr OS in 47 pts treated with HDC and ASCT (Br J Hem 2011). Our multicenter experience with RIT plus HDC (Yttrium 90 ibritumomab tiuxetan plus BEAM; carmustine, etoposide, cytarabine, melphalan "ZBEAM") demonstrated the safety and efficacy of the regimen in diffuse large cell lymphoma (DLCL). Therefore, the regimen was explored in other subtypes of NHL. Herein we report the outcome of 57 pts with TF NHL treated with ZBEAM conditioning and ASCT at three centers (City of Hope USA n=20, VUMC the Netherlands n=31, Chaim Sheba Med Center, Israel n=6.) between 2003- 2011. Methods: Histological confirmation of transformation was defined as dx of DLCL in pts with either a prior history or concomitant dx of follicular NHL. Results: Median age at ASCT was 59.6 yrs (range 41-69). Median number of prior regimens 2 (range 1-6), all pts received rituximab in at least one regimen. Disease status at ASCT: 1st CR 29, 1stPR 7,1st rel 9, IF 5, 2nd CR 5, 2nd rel 1, >3CR 1. Median time from TF NHL dx to ASCT was 7.7 mo (range 2.8-116). Pts engrafted white cells at median of 12 days (range 8-33). Non relapse mortality was 3.5%. There were two second malignancies: 1 MDS and 1 SCC Skin. Median f/u for living pts was 29 mo (range 7-100). Two year PFS was 69.67% (95%CI 59.39 - 77.83) and OS 90.29% (95% CI: 79.63 - 95.52). On univariate analysis, number of prior regimens, time from TF NHL dx to ASCT and history of marrow involvement were not significant for PFS and OS. Disease status at ASCT was significant for PFS in 1st CR vs relapse disease ( p=0.03) The relapsed pts had a significant increase in risk of relapse/progression or death post ASCT compared to the 1CR patients. [HR = 2.9, (95% CI: 1.07 - 7.9)]. Conclusions: ZBEAM conditioning with ASCT is an active treatment for pts with TF NHL, and is particularly efficacious as consolidation for pts in 1st CR.

Anti-CD45 Pretargeted Radioimmunotherapy Prior to Bone Marrow Transplantation without Total Body Irradiation Facilitates Engraftment From Haploidentical Donors and Prolongs Survival in a Disseminated Murine Leukemia Model

s / Biol Blood Marrow Transplant 19 (2013) S211eS232 S228 chemotherapy was HIDAC (1-3 grams/m2 for 6-8 doses)/ Etoposide(15-40mg/kg) in 16 patients and growth factor alone in one patient. Median time from diagnosis to ASCT was 4.2 (range 3.6-7) months. Preparative regimen for ASCT was Busulfan (3.2mg/kg x 4)/Etoposide (60 mg/kg) in 12 patients and high dose melphalan in 5 patients. The median CD34 cells infused was 4.9 x 10e6/kg (range 2.8 to 15.9).All patients engrafted with a median time to neutrophil engraftment of 11 (range10-12) days. The median time to platelet engraftment was 20 (range15-40) days. The median length of inpatient stay during the ASCT admission was 14 (range 10-25) days. One patient died of progressive disease 14 months post ASCT. Two patients died in remission on day 53 (sepsis) and day 836 (unknown cause) post ASCT. Fourteen patients (82%) are currently alive in complete remission. at a median follow-up of 20 (range 140) months post ASCT. Conclusion: Consolidation of good risk AML patients with ASCT following induction of complete remission is safe and effective in preventing relapse in good risk AML patients.

Reconstitution of Lymphocyte Subsets and Outcomes After Matched and Mismatched Hematopoietic Stem-Cell Transplantation

Abstract 4485 Allogeneic stem-cell transplantation (ASCT) is curative for many malignant and nonmalignant hematological disorders. Limitations of expanding this form of treatment are related primarily to non-relapse mortality (NRM) associated with reconstituting the recipient's immune system. We aimed to study reconstitution of lymphocyte subsets after matched and mismatched transplantation. Lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, CD56, CD25, CD45RA, CD45RO) were evaluated by flow cytometry at 1,3,6 and 12 months (mo) post-ASCT. Lymphocyte recovery was determined using means at each time point and group differences were assessed using analysis of variance. Kaplan-Meier survival curves were used to estimate time-to-event outcome measures and the log-rank test was used to evaluate differences between groups. 100 patients (pts) were included in the study. 25 pts received a matched sibling donor transplant (MSD), 20 pts a 10/10 MUD, 18 pts a 9/10 MUD, 9 pts a T cell depleted haploidentical (TCD haplo), and 28 a T cell replete haploidentical donor (TCR haplo). 53 pts received bone marrow and 47 had peripheral blood stem cells. Most patients were treated for acute leukemia (AML 41, ALL 23), 16 MDS, 6 CML, 4 CLL, 5 lymphoma. Median age was 43 years (range: 20–71). The median follow-up was 13.6 mo. 60 pts were alive and disease-free at last follow-up and 28 pts died 75% due to relapse. Non-relapse mortality (NRM) was 6% for the entire cohort. Overall, alive pts (vs who died) had higher mean CD3 (615 vs 349, p=0.03 on day 90), CD8 (427 vs 187, p=0.03 on day 90), CD4 (391 vs 54, p=0.01, on day 365) cells, and lower mean CD56 cells (178 vs 300, p=0.01, on day 30) post ASCT. Pts who progressed (vs did not), had lower 1 year mean CD4 cells (123 vs 394, p=0.02), lower mean CD3 cells (359 vs 1147, p=0.06), with no differences in CD8, NK, and CD45RA. NRM was associated with higher mean NK numbers at 6 months (499 vs 188, p=0.01) and with lower mean CD3 at day 90 (184 vs 557, p=0.07). T-cell recovery occurred most rapidly in MSD transplants ([Figure1][1]C), and compared with 10/10 MUD had higher mean CD3 cells in the first mo (1085 vs 510, p=0.01), CD4 in the first 6 mo (310 vs 147, p<0.01 day 180) and CD4CD45RA in the first 6 mo (105 vs 31, p=0.02 on day 180). Interestingly, we have found that higher CD4CD25 cell numbers recovered early and most rapidly in the MSD transplants, which may partly explain a lower incidence of GVHD in this group. Overall, TCR haplos had a similar pattern of T-cell recovery and outcomes as 10/10 MUDs ([Figure1][1]C-E). There was a significant delay in CD3 recovery between MSD and TCR haplos in the first 3 mo (mean 779 vs 483, p=0.04 on day 90), CD4 (mean 270 vs 170, p=0.03 day 90) and in the first 6 months for CD45RA (mean 105 vs 28, p=0.01 on day 180), while these differences were significant only at day 30 for CD8 cells (mean 703 vs 88, p<0.01). No significant differences in T cell subsets were found between 10/10 MUD and TCR HaploSCT for CD3, CD4, CD8, CD45RA and CD4CD25 for any time points. Of all types of transplant, TCD haplos had most impaired T-cell reconstitution and worst outcomes ([Figure 1][1]A and [1][1]B). As previously reported it was characterized by rapid early NK cell recovery and delayed CD3, CD4, CD8 reconstitution. Interestingly, pts surviving 6–9 months post-transplant recovered CD3, C4, CD8 cells; however, naive T-cell recovery remained impaired for more than 1 year post-transplant, suggesting that T cell recovery comes predominantly from the memory T cell compartment. In conclusion, these results suggest that recovery of lymphocyte subsets may vary widely with the type of transplant, may correlate with outcomes, and it is important to be further explored in this setting. ![Figure][2] Disclosures: No relevant conflicts of interest to declare. [1]: #F1 [2]: pending:yes

Reconstitution of Lymphocyte Subsets and Outcomes After Matched and Mismatched Hematopoietic Stem-Cell Transplantation

Abstract 4485Allogeneic stem-cell transplantation (ASCT) is curative for many malignant and nonmalignant hematological disorders. Limitations of expanding this form of treatment are related primarily to non-relapse mortality (NRM) associated with reconstituting the recipient's immune system. We aimed to study reconstitution of lymphocyte subsets after matched and mismatched transplantation.Lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, CD56, CD25, CD45RA, CD45RO) were evaluated by flow cytometry at 1,3,6 and 12 months (mo) post-ASCT. Lymphocyte recovery was determined using means at each time point and group differences were assessed using analysis of variance. Kaplan-Meier survival curves were used to estimate time-to-event outcome measures and the log-rank test was used to evaluate differences between groups. 100 patients (pts) were included in the study. 25 pts received a matched sibling donor transplant (MSD), 20 pts a 10/10 MUD, 18 pts a 9/10 MUD, 9 pts a T cell depleted haploidentical (TCD haplo), and 28 a T cell replete haploidentical donor (TCR haplo). 53 pts received bone marrow and 47 had peripheral blood stem cells. Most patients were treated for acute leukemia (AML 41, ALL 23), 16 MDS, 6 CML, 4 CLL, 5 lymphoma. Median age was 43 years (range: 20–71). The median follow-up was 13.6 mo. 60 pts were alive and disease-free at last follow-up and 28 pts died 75% due to relapse. Non-relapse mortality (NRM) was 6% for the entire cohort.Overall, alive pts (vs who died) had higher mean CD3 (615 vs 349, p=0.03 on day 90), CD8 (427 vs 187, p=0.03 on day 90), CD4 (391 vs 54, p=0.01, on day 365) cells, and lower mean CD56 cells (178 vs 300, p=0.01, on day 30) post ASCT. Pts who progressed (vs did not), had lower 1 year mean CD4 cells (123 vs 394, p=0.02), lower mean CD3 cells (359 vs 1147, p=0.06), with no differences in CD8, NK, and CD45RA. NRM was associated with higher mean NK numbers at 6 months (499 vs 188, p=0.01) and with lower mean CD3 at day 90 (184 vs 557, p=0.07). T-cell recovery occurred most rapidly in MSD transplants (Figure1C), and compared with 10/10 MUD had higher mean CD3 cells in the first mo (1085 vs 510, p=0.01), CD4 in the first 6 mo (310 vs 147, p<0.01 day 180) and CD4CD45RA in the first 6 mo (105 vs 31, p=0.02 on day 180). Interestingly, we have found that higher CD4CD25 cell numbers recovered early and most rapidly in the MSD transplants, which may partly explain a lower incidence of GVHD in this group. Overall, TCR haplos had a similar pattern of T-cell recovery and outcomes as 10/10 MUDs (Figure1C-E). There was a significant delay in CD3 recovery between MSD and TCR haplos in the first 3 mo (mean 779 vs 483, p=0.04 on day 90), CD4 (mean 270 vs 170, p=0.03 day 90) and in the first 6 months for CD45RA (mean 105 vs 28, p=0.01 on day 180), while these differences were significant only at day 30 for CD8 cells (mean 703 vs 88, p<0.01). No significant differences in T cell subsets were found between 10/10 MUD and TCR HaploSCT for CD3, CD4, CD8, CD45RA and CD4CD25 for any time points. Of all types of transplant, TCD haplos had most impaired T-cell reconstitution and worst outcomes (Figure 1A and 1B). As previously reported it was characterized by rapid early NK cell recovery and delayed CD3, CD4, CD8 reconstitution. Interestingly, pts surviving 6–9 months post-transplant recovered CD3, C4, CD8 cells; however, naïve T-cell recovery remained impaired for more than 1 year post-transplant, suggesting that T cell recovery comes predominantly from the memory T cell compartment.In conclusion, these results suggest that recovery of lymphocyte subsets may vary widely with the type of transplant, may correlate with outcomes, and it is important to be further explored in this setting. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Feasibility and Outcome of High Dose Therapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Lymphoma in the Geriatric Population

AbstractAbstract 4269 Introduction:High-dose chemotherapy with autologous stem cell rescue (HDT-ASCT) remains the standard of care for patients with chemosensitive, relapsed diffuse large B-cell lymphoma (DLBCL). Because of concern for unacceptable toxicity and therefore inferior outcomes, geriatric patients (age >= 70) with relapsed DLBCL are typically not considered candidates for HDT-ASCT in clinical practice and have largely been excluded from clinical trials examining the role of HDT-ASCT with curative intention. There is a paucity of data in the transplant literature describing outcomes (with long-term follow up) of geriatric DLBCL patients undergoing HDT-ASCT in the relapsed-refractory setting. Methods:Utilizing Kaplan-Meier survival and Cox regression analyses, we conducted a two-center (John Theurer Cancer Center and Weill-Cornell Cancer Center) retrospective cohort study to evaluate the outcome of geriatric patients (age >= 70) with chemosensitive, relapsed-refractory DLBCL who underwent HDT-ASCT between 1994 and 2011. The primary study endpoint was overall survival (OS) assessed by chart review and SSDI database. As a secondary endpoint, we examined survival outcomes of geriatric patients with relapsed-refractory DLBCL who underwent HDT-ASCT in the rituximab era (transplant performed after year 2000). Results:75 geriatric patients with lymphoma (DLBCL 71%, MCL front-line consolidation in CR 11%, HL 5%, FCL 4%, PTCL 4%) were identified in our combined transplant outcomes database of which 52 underwent HDT-ASCT (n=40 JTCC, n=12 Cornell) for relapsed-refractory DLBCL representing 30 deaths and 1522 total months at risk (median follow up 18.4 months). Baseline characteristics included: median age at time of salvage and ASCT was 72, (range 70–86), ECOG PS 1 (range 0–2), ethnicity (90% caucasian), sex (65% male), hematopoietic cell transplant-co-morbidity (HCT CI) index score (median=1), conditioning regimen (BEAM 49%, BEAC 33%, 16% CBV, 2% Cy-TBI). With a median follow up of 18.4 months, the median OS for the entire cohort was 35.7 months with a 100 day mortality of 8.6% (95% CI 7.4–9.3%). The median OS for DLBCL patients who underwent HDT-ASCT in the rituximab era was 43 months (Figure). In univariate analysis, age (continuous variable, p=.15), patient sex (p=.9), HCT CI score (continuous variable, p=.4) were not associated with inferior survival. Conclusions:HDT-ASCT in a geriatric patient population is feasible with similar outcome as younger pts as shown by the following: 1.ASCT was associated in our series with comparable OS to younger patients with relapsed lymphoma.2.For patients with relapsed/refractory DLBCL treated with rituximab in the front line setting, outcomes are similar to published data (CORAL study, EFS at 3 yr=21%) in younger patients.3.Overall given the incidence of NHL in elderly (reported increase >500% in > 80y over last 10 years), a larger number of pts might have to be considered to salvage and ASCT.4.Additional prospective studies should explore optimization of HDT-ASCT in the geriatric setting including upcoming novel strategies from combination with new biologicals, to drug antibody conjugates as well as maintenance post ASCT to help continue improve the outcome in this population. [Display omitted] Disclosures:Mato:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goy:Milennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; J & J: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Feldman:Merck: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Allos: Speakers Bureau.

Myeloma ASH 2010 highlights

the questions and for the sake of clarity they have been discussed together. These results should be examined in the context of the current approaches for managing myeloma. Broadly, the treatment strategy for myeloma consists of an ‘‘induction therapy’’ aimed at rapid control of the disease followed by a consolidation strategy that may include stem cell transplant (SCT), followed by maintenance strategies where appropriate [2]. This should be complemented by full supportive care to ameliorate the effect of myeloma-related end organ damage and other potential complications. We present some of the most exciting findings form the meeting, grouping them in the context of treatment steps for better perspective of their impact on daily practice. Initial Therapy of Myeloma The results from several Phase 2 and Phase 3 trials were presented looking at the efficacy of different combinations in previously untreated patients. In general, the different trials examined two, three, and four drug combinations that included both new and old drugs. Cavo et al. presented the results of a randomized trial that compared bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone as initial therapy of newly diagnosed MM followed by double autologous stem cell transplantation and further consolidation therapy [3]. Initial treatment consisted of three 21-day cycles of thalidomide (100–200 mg/day) along with dexamethasone (320 mg/cycle) with (TD) or without bortezomib 1.3 mg/m 2 twice weekly (VTD). Patients then had stem cells collected with cyclophosphamide and growth factors, followed by tandem ASCT with Mel 200 conditioning. Patients received thalidomide and dexamethasone between the ASCT and then received three 5-week cycles of thalidomide and dexamethasone with or without bortezomib 1.3 mg/m 2 weekly. Overall, 236 patients were randomized to VTD and 238 to the TD arm. There was a progressive increase in the depth of response during each phase of therapy with nCR or better rates of 31%, 52%, 55%, and 62% after induction, 1st ASCT, 2nd ASCT, and consolidation respectively with VTD; all of which was significantly better than TD (11%, 31%, 41%, and 45%, respectively). Addition of bortezomib to TD resulted in a 39% relative reduction in the risk of progression with no difference in the overall survival after a median follow-up duration of 36 months. Subgroup analysis showed that the impact of t(4;14) on progression free survival (PFS) was not evident among patients getting bortezomib, unlike TD suggesting a beneficial effect of the drug on patients with this high-risk

Impact of Time to Lymphocyte Recovery on Survival Post Autologous Stem Cell Transplantation.

AbstractAbstract 4540 Introduction:Several studies have suggested that the peripheral blood absolute lymphocyte count (ALC) at arbitrary time points after ASCT is associated with improved survival and decreased relapse rate. Most reports have focused on one type of hematological malignancy, and different time points (i.e. day 15, day 21) and ALC values (> 0.35×109/L, > 0.5×109/L) have been studied. We hypothesized that the immune recovery post ASCT is an important predictor of long term outcome independent of disease, and that more important than the value of ALC at a specific time point, is the time to lymphocyte recovery post-ASCT. Methods:The medical records of patients that underwent ASCT at our institution from January 2005 until May 2010 were reviewed and information on ALC count at day 15 and time to lymphocyte recovery was retrieved. Lymphocyte recovery was defined as the first of at least two consecutive days with > 0.5×109/L lymphocytes on the peripheral blood. Overall survival was defined as time from ASCT until death from any cause. OS was estimated by Kaplan-Meier and compared by logrank. Cox proportional hazards models was used to determine covariates associated with OS in a multivariate analysis. Variables were entered and selected in a backwards fashion with a p cutoff of 0.05. Results:Ninety-two patients were analyzed. Diagnosis included: multiple myeloma (N=35), non-Hodgkin's lymphoma (N=33), solid tumors (N=8), Hodgkin's lymphoma (N=8), acute myeloid leukemia (N=4), amyloidosis AL (N=3) and chronic myeloid leukemia (N=1). Median age was 55 years (range 3–74 years). OS at 2 years for the entire cohort was 51% (95% CI 37–66%). There were 47 patients (51%) with an ALC at day 15 (ALC-15) ≥ 0.5×109/L, and these patients had a significantly superior OS compared to patients with an ALC-15 < 0.5×109/L (2-years OS: 68% vs. 35%, p=0.01). Median time to lymphocyte recovery was 15 days (range 8–314 days). Patients with a rapid (≤ 15 days) lymphocyte recovery had superior OS compared to those with a slower (> 15 days) lymphocyte recovery (2-years OS: 66% vs. 31%, p=0.002). Median OS for those with a quick recovery was not reached, while for patients with a slow recovery was 16 months (95% CI 3–29 months). In a Cox proportional hazards analysis, the following variables were added: age, diagnosis of multiple myeloma (yes vs. no), ALC-15 < 0.5×109/L (yes vs. no) and slow lymphocyte recovery (yes vs. no). Only diagnosis of multiple myeloma (hazard ratio [HR] 0.25 [95% CI 0.09–0.67], p=0.006) and slow lymphocyte recovery (HR 3.18, [95% CI 1.44–7.03], p=0.004) were associated with OS, while ALC-15 was not. Conclusion:Our results suggest that the kinetics of lymphocyte recovery have an important impact on survival post-ASCT. Our findings need to be confirmed in other cohorts. Strategies to modulate immune function post-ASCT should be the subject of future studies. Disclosures:No relevant conflicts of interest to declare.

Outcome In Follicular Lymphoma (FL) Patients (pts) Relapsing After Autologous Stem Cell Transplantation (ASCT): Allografting Vs. Conventional Therapy

AbstractAbstract 3510 Background:The outcome in FL pts relapsing after ASCT has not been well studied. While the use of nonmyeloablative allogeneic stem cell transplantation (NST) has been promising in this setting, one could not underestimate the results of selective inclusion criteria. Methods:All patients with FL who experienced a relapse after ASCT at The University of Texas M. D. Anderson Cancer Center between 1997 (the initiation of the rituximab and NST era) and 2007, were analyzed. Results:Fifty pts were identified. Fifteen (30%) pts underwent NST after ASCT relapse (Group A); 25 (50%) pts (Group B) met the eligibility criteria for NST but were not allotransplanted due to either physician/pt preference (n=14), lack of suitable donors (n=5), insurance requirements (n= 3), other causes (n=3). Ten (20%) pts (Group C) were not eligible for NST due to refractory disease or co-morbidities. At the time of progression after ASCT, the comparison of pts who were considered for NST showed that Group A pts and Group B pts had a comparable age [median 57 years(range, 45–64) vs 58 years (range, 40–70), p=0.7, respectively], serum LDH level (p=0.1), # of extranodal sites of disease (p=0.4), marrow involvement (p=0.1), and stage III/IV (p=0.2). The histology subtypes were also equally distributed in both groups (FL grades 1, 2, and 3 were found in 27%, 40% and 30% of Group A pts, respectively, and in 16%, 44% and 40% of Group B pts, respectively). The majority of pts in Groups A and B had a good ECOG PS of 0–1 (100% vs 96%, respectively). The median time from ASCT to progression was 16 months (range, 4–42) in Group A, and 19 months (range, 3–99) in Group B. Group A pts underwent their NST at a median of 8 months after their ASCT relapse. At their progression post ASCT, pts in Group B were treated with either rituximab as a single agent (n=12, 48%), or combination chemo-antibodies (n=7, 28%); the therapy received in the remaining 6 (24%) pts was unknown. With a median follow-up time of 49 months (range 23–113 months) for Group A, and 37 months (range, 17–130 months) for Group B, the actuarial survival rates at 4-year were 73%(%95 CI, 42–89) and 71% (%95 CI, 46–86), respectively, (Figure, p = 0.9). The causes of death in Group A were related to infection (1), organ failure (1), progression (2), and unknown (1). Five pts in Group B died of progression and one died of secondary leukemia. Pts in Group C had a median survival time of 7 months; only 2 pts of this group were still alive at the time of this analysis was made. [Display omitted] Conclusions:Single institution results show that 30% of pts with FL relapsing after ASCT undertook an allotransplant. While allogeneic NST is an effective therapy for these pts, a significant proportion of pts can be observed for several years before an allotransplant should be considered. Disclosures:No relevant conflicts of interest to declare.

Achievement a Negative 18-FDG/PET Status at the End of Procedure by Tailored Treatment According Pre-Transplantation Pet Status in Lymphomas Improve 5 Years-OS and EFS.

In patients (pts) with non Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) with poor prognosis factors, pre-transplantation (ASCT) 18-fluorodeoxyglucose (FDG)-positron-emission tomography (PET) status is important for evaluation of response and predicting the outcome. A positive pre-ASCT PET (+PET) indicated a high risk (HR) of relapse which was increased by a positive post-ASCT PET. For these patients additional therapy (salvage therapies prior ASCT, targeted radiotherapy, second transplant or new treatment approaches) will be required (Spaepen K 2001, Filmont JE 2003; Svoboda J 2006, Mounier, 2007). In a french regional network, we try to obtain a negative metabolic status with additive « targeted-therapy », before or after the ASCT, in the hope to improve the clinical outcome for these HR NHL/HD.Objective: The study assessed the impact of tailored therapy according to pre-transplantation FDG-PET status on pts outcome after high-dose chemotherapy and ASCT.Patients & Methods: We performed a retrospective analysis of pts included according three criteria: 1) histologically proven malignant lymphoma (NHL/HD) with a metabolic active disease in PET imaging 2) planned to receive an ASCT for HR factors according international recommendations (de novo initial aaIPI III/IV or not in CR after front line chemotherapy or in early and unfavorable relapse; 3) having a PET prospectively performed prior and after ASCT on a CDET replaced in 2005 by a PET/CT (Siemens). The metabolic imaging interpretation had been performed by 2 experienced nuclear physicans first blinded to clinical and CT scan then discussed in multidisciplinary team. + PET defined as any focal or diffuse area of increased activity in a location suspect for residual disease and -PET if any metabolic activity according revised Cheson criteria. Survival analysis were performed using Kaplan-Meier method for event free survival (EFS), overall survival (OS).Results: For 95 consecutive pts treated from 05/1999 to 12/2006 18 HD and 77 NHL, an ASCT has been planned either in initial HR prognostic score (n=39), primary refractory disease (n=31), or in relapse (n=25). First line therapy were mainly ABVD for HD and ACVBP/CHOP +/− Rituximab for NHL. A pre-ASCT -PET was obtained in 52 pts (55%) and 43 pts (45%) remained pre-ASCT +PET. Additional salvage chemotherapy (MINE or DHAP(+/−R) most frequently) obtained a - PET status from pre-ASCT +PET in 9/43 pts (21%) prior the ASCT. ASCT has been performed for all these HR pts with a conditioning regimen mainly BICNU-Etoposide-Aracytine-Melphalan (BEAM). After ASCT, 22/43 pre-ASCT +PET pts were converted in a post-ASCT -PET status. Residual disease of post-ASCT +PET pts was treated by targeted radiation (n=11) or by a second transplant (n=2). One pre-ASCT -PET converted to positive (1/52). At the end of procedure, we obtained a –PET status in 88 pts (92%), persistant + PET in 7 pts (7%) (3 PR/4 PD). With a median follow-up of 4.14 years (range 0.61–9.48) since diagnosis, 15/43pts (35%) pre-ASCT +PET and 14/52pts (26%) pre-HDT/ASCT -PET pts relapsed. Mortality was 23% (22/95pts range -PET : 11/52 (21%) and +/−PET 11/43 (25%) respectively and 4/7 (57%) resistant +/+PET). In –PET and in +/−PET median OS and EFS were not reached, 5yOS was 79% and 73% (p=0.7) and 5 y-EFS 62% and 54% respectively (p=0.2). In residual post-ASCT+PET, median OS was 4,5 months.Conclusion: PET-guided consolidative therapy prior or post ASCT in patients with HR lymphoma is routinely feasible and could obtain a negative status in 92% of pts at the end of procedure and reduce relapses with encouraging results in terms of OS and EFS with a 5-y median follow-up. Next step is now on-going: including pts in multicentric PETdesigned trials to confirm prospectively the crucial role of the metabolic imaging to determine which is the best tailoring therapy.

Age under 40 Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transplant Despite High Response Rates.

BACKGROUND: Multiple myeloma (MM) only occurs in 2% of patients under the age of 40. It has been reported that this young cohort of patients have a superior overall survival when compared to those over the age of 40.OBJECTIVE: To evaluate the clinical and laboratory features of patients ≤40 years of age at diagnosis of MM and to compare survival outcomes to patients >40 years of age.METHODS: Retrospective institutional review of all patients ≤40 years of age at time of diagnosis of MM that had underwent upfront ASCT at PMH from January 1, 1990 to July 31, 2007. Outcomes were compared to patients >40 years of age who had also undergone ASCT as upfront therapy.RESULTS: 37 patients ≤40 years of age were identified. Twenty patients were male. Immunoglobulin subtype was as follows: 49% had IgG, 19% light chain,16% IgA, 8% IgD, and 5% IgG plasma cell leukemia. The main presenting clinical feature was bone pain (63%). 73% had radiological evidence of bony disease at diagnosis and 53% of these patients required radiation prior to ASCT. Clinical features included anemia in 81%, renal insufficiency in 39% and hypercalcemia in 28%. Conditioning regimens for ASCT were high dose melphalan (200mg/m2) alone in 25 pts, VP-16 & melphalan +/− TBI in 8 pts, bleomycin & cyclophosphamide in 3 pts, and in 1 pt it was unknown. Median time to engraftment of neutrophils (>0.5 x 109/L) and platelets (>20 x 109/L) was 11 days (range 8–18) and 12 days (range 0–54), respectively. Median duration of hospitalization was 17 days (range 10–54). No treatment related mortality was experienced. Response to ASCT was as follows in 29 evaluable pts: CR in 10 (34.5%), PR in 13 (44.8%), MR in 1 (3.4%), SD in 3 (10.3%), and PD in 2 (6.9%). Five patients underwent a tandem ASCT. Maintenance therapy was instituted in 11 pts. Median progression free survival (PFS) post ASCT was 23.0 months, which is similar to the PFS of 28.5 months in patients over 40 (p=0.559). There was also no difference in median overall survival (OS) from date of ASCT between the two groups (6.6 years in pts ≤40, 6.7 years in pts >40; p=0.797).CONCLUSION: Young patients with MM present with advanced disease as evidenced by anemia, bone involvement and hypercalcemia. ASCT yields high response rates, but PFS post ASCT is less than 2 years. Although young age has been historically been considered to be a positive prognostic marker, OS post ASCT is only 6.6 years, which is equivalent to those >40 years of age. Strategies to better the outcomes of young patients with MM are required.

Long-Term Outcome of Autologous Stem Cell Transplantation (ASCT) for Hodgkin Lymphoma (HL) in the ABVD Therapeutic Era.

ASCT is the standard therapy for relapsed HL. However, the majority of published studies suggesting benefit of ASCT for relapsed HL include relatively young patients (pts) with favorable prognostic features, and have relatively short follow-up. Moreover, very little data exists on the outcome of pts who experience progression of HL after ASCT. To determine the long-term outcome of ASCT in the modern, “ABVD-era”, and the impact of allogeneic transplantation in pts who fail ASCT, we reviewed all pts with HL who were treated with ASCT between 1990 and 2005 at the University of Rochester. 117 pts (44% female; 89% Caucasian) with documented HL were treated with ASCT for relapsed or refractory HL. At ASCT, median age was 34 years (range 19–66). 75% of these pts were treated initially with ABVD or MOPP-ABVD hybrid therapy. Histology was: NS (n=82), mixed cellularity (n=20), LP (n=6), LD (n=3), and classical NOS (n=6). 32% of pts had relapsed within 1 year of initial therapy, and 25% were refractory to therapy prior to ASCT. Conditioning regimens at ASCT were BEAC (n=80); BEAM (n=28); CBV (n=1); Cy/TBI (n=8). 49% of pts received XRT following ASCT. Median follow-up of entire cohort exceeded 5 years. At 5 years, overall survival (OS) for entire population was 50%, and event-free survival (EFS) was 38%. As expected, pts older than 45 yrs of age (n=21, p=0.06) and pts who relapsed within 1 year of initial therapy (p=0.0004) had an inferior OS after ASCT. In total, 49 pts have died; of these, 30 pts died of HL. 19 deaths occurred in remission: 9 were conditioning-related within the first 100 days of ASCT; 3 were from secondary malignancies (2 AML, 1 NHL), 1 from colitis, 1 from pulmonary fibrosis, and 5 with unknown cause. 9 of the deaths occurred more than 5 yrs after ASCT. 54 pts had progression of HL post ASCT; median survival for this group was 2.1 years after ASCT. 14 of these pts (26% of pts who failed ASCT) underwent allogeneic transplantation. 8 of these patients have died: 5 from progression of HL, 2 from pulmonary toxicity, and 1 from GVHD. Of the 5 remaining pts, 1 has progression of HL after allogeneic transplantation, and 3 have chronic GVHD. We conclude that ASCT remains a curative option for patients relapsing after ABVD, as there is a clear plateau on the relapse free survival curve after 5 years. Primary refractory disease and older age at ASCT dramatically affects outcome. In this modern era, deaths in remission after ASCT remain a significant problem due to both short-term and long-term toxicities of therapy. The risk of progression of HL persists until 5 years after ASCT, emphasizing the importance of prolonged follow-up. Although some pts who progress with HL after ASCT may live for years with a seemingly indolent form of HL, there is no plateau on the survival curve, and the majority of pts who progress after ASCT are not alive 2 years post ASCT. Allogeneic transplantation has not yet had a significant impact on OS for this group of pts. Novel approaches are clearly needed for the majority of pts who progress after ASCT, particularly older patients at ASCT and patients with primary induction failure.

Maintenance Therapy with Low Dose Thalidomide, Dexamethasone and Clarithromycin (Biaxin) (BLT-D) Following Autologous Transplant (ASCT) for Multiple Myeloma (MM).

Relapse remains a major problem after a standard ASCT for MM. Strategies to prevent relapse have included post transplant maintenance therapy. M Coleman et al (Leukemia and Lymphoma 43:1777–1782, 2002) pioneered a regimen of BLT-D to treat in a non-transplant setting MM and reported a high CR/PR response rate (93%). Since the BLT-D regimen showed significant disease response, it seemed reasonable to study this regimen as maintenance therapy after ASCT. Between 7/2003–1/2006, 23 patients (stage II, n=6 and stage III (n=17) were treated. 26% of patients had poor prognostic cytogenetics. 61% had elevated beta 2 microglobulin at initial diagnosis; 30% still had elevated beta 2 microglobulin at time of ASCT. 48% of the patients had received Thalidomide therapy before ASCT. All were conditioned for ASCT with melphalan 200 mg/m2. 30–120 days after recovery from the acute toxicity of ASCT, patients were treated with Biaxin 250 mg po bid, Dexamethasone 20 mg po q week and Thalidomide beginning at 50 mg po daily for 14 days, then increased to 100 mg po daily. After one year of combination therapy, Biaxin and Dexamethasone were stopped and Thalidomide was continued as long as tolerated or until disease progression. The median time to starting therapy was 102 days (range 40–120) post ASCT. Neuropathy was the most common toxicity. Four patients stopped therapy because of significant peripheral neuropathy and four patients required dose reduction of Thalidomide because of neuropathy. Eight patients had reduction in Dexamethasone dosing because of toxicity. One patient stopped Biaxin for rash. Number of infections seen included pneumonia (n=3), viral upper respiratory infection (n=2), sinusitis (n=1) and bronchitis (n=3). One patient withdrew from therapy to undergo elective second ASCT. Three patients have died: infection (n=1), MM progression (n=1) and complications of second ASCT (n=1). In patients who still had detectable MM after ASCT prior to beginning BLT-D therapy, 46% of the evaluable patients to date have been shown to go into complete remission on BLT-D therapy. Three patients have progressed. 18 (78%) out of 23 patients remain alive without disease progression. Median follow-up is 20.5 months (range 6–25). Further follow-up is needed to determine the effect of BLT-D upon relapse and survival of MM ASCT patients.

High Dose Therapy / ASCT with Rituximab for In-Vivo Purging and Post-ASCT Consolidation in Relapsed Follicular Lymphoma Achieves Prolonged Clinical and Molecular Remissions.

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is associated with prolonged remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT predicts durable remissions and is a desirable endpoint. Rituximab (R) as an in vivo purge prior to HDT/ASCT and as consolidation after ASCT may help achieve this. To study this question, patients with relapsed FL were enrolled in a prospective, non-comparative phase II study between January 1998 and April 2000.Methods: 23 consecutive patients age <65 yrs with <3 relapses underwent HDT/ASCT with CBV (Cyclophosphamide, BCNU and VP-16) following salvage with CHOP or DHAP. Patients achieving ≥75% reduction in bulk and <15% marrow involvement underwent stem cell mobilization with chemotherapy plus G-CSF 10 μg/kg daily x 5. R 375 mg/m2 was given as a single-dose purge prior to collection, and repeated as 4 weekly courses at 2 and 6 months post-ASCT. Samples for PCR detection of minimal residual disease (MRD) were taken from stem cell grafts, as well as blood and marrow for all patients with detectable disease at baseline. Response assessments were clinical, laboratory and radiologic, and analysis was intention-to-treat.Results: Median cohort age at assessment was 50 yrs (32–57). Median number of prior regimens was 3 (1–7) and total treatment cycles was 9 (3–28). Median response duration to the preceding regimen was 10 months (1–86). Transplants were a median 2.4 years after diagnosis. At median follow-up of 4.5 yrs (1.3–6.3), there have been 10 relapses at a median of 2.8 yrs. 3 patients have died, 2 with relapse and one of presumptive sudden cardiac death. Significant toxicities were seen: 11 episodes of pneumonia (1 fungal), 4 episodes of herpes zoster (1 grade 3), 4 early episodes of grade 3/4 interstitial pneumonitis, and 1 episode each of grade 4 TTP and grade 3 optic neuritis. One patient developed AML at 4.7 years post-ASCT. Immune recovery has been delayed; at 600 days post ASCT, 16/18 (89%) of evaluable patients had not recovered IgG levels to normal. At baseline, 12/23 patients had detectable markers by PCR analysis (sensitivity 0.01%) for t(14;18) or patient-specific VDJ rearrangements in marrow or blood. Of these, all achieved at least a brief molecular remission in blood and marrow, 11/12 doing so pre-R consolidation. 5/12 patients have since relapsed at a median 3 yrs (2–4.5) post ASCT. Molecular relapse preceded clinical in 3/5 cases. 6/12 have had prolonged (median 4.8 yrs, range 3–5) molecular and clinical remissions. Median event-free survival for all patients is 63 months, with median overall survival not reached.Conclusions: HDT/ASCT with R for in vivo purging and post-ASCT consolidation for relapsed FL is feasible and associated with prolonged clinical and molecular remission. Delay in recovery of humoral immunity may play a role in the high incidence of infectious complications. A single infusion of Rituximab for in-vivo purging did not eradicate PCR detectable disease in the graft, although sustained molecular remissions of at least 24 months were achieved in 75% of evaluable patients post transplant, possibly due to post ASCT Rituximab consolidation. Whether this translates into survival benefit will require longer follow-up and further comparative studies.

A Simplified Real-Time PCR Method for the Quantification of Minimal Residual Disease in Follicular Lymphoma.

High-dose therapy and autologous stem-cell transplantation (HDT/ASCT) is associated with long remissions in relapsed follicular lymphoma (FL). Molecular remission in the graft and post ASCT is predictive of durability of remission. Thus, a simple, reliable method of quantitation of minimal residual disease (MRD) would improve prognostication in these patients. Real-time polymerase chain reaction (PCR) can quantitatively detect FL markers in blood and BM with a reproducible sensitivity of 0.01%. Fluorescent probe systems are used to perform real-time PCR; however, these techniques are expensive and do not allow melt curve analysis of the PCR product. We describe here a less expensive SYBR green detection method which also enables us to check clonal identity, and yields sensitive, reliable quantitative results for monitoring MRD. We compared our real-time PCR results with previously determined conventional nested PCR results in a series of samples collected from patients enrolled in one of our clinical trials.Methods: Patients with relapsed FL (n=14) were enrolled in a prospective study of HDT/ASCT followed by maintenance Interferon-a 3x106 U/m2 SC 3 x weekly for 2 yrs. DNA extracts were collected at enrolment from samples of lymph node, BM and blood to determine detection of BCL2/JH translocation. Stem-cell graft DNA and serial post-ASCT blood and BM DNA samples were collected. BCL2/JH was qualitatively determined by nested PCR using standard primers and analyzed by gel electrophoresis. For patients in whom BCL2/JH was not detectable, clone-specific IgH region primers were used where possible. Quantitative PCR was performed using QuantiTect SYBR Green kits. Melt curve analysis was performed to confirm amplification specificity and clonal identity of each sample. All samples were analyzed in triplicate for accuracy.Results: At a median follow-up of 75 months (9–91), 10/14 patients are alive. Of these, 3 are free from progressive disease. Median progression-free survival is 42 months; median overall survival has not been reached. We were successful in defining molecular markers for 12/14 patients. In 11/12, we were able to PCR amplify the BCL2/JH translocation. In one patient, allele-specific clonal IgH was analyzed with patient specific oligonucleotides. Median BCL2/JH contamination of stem-cell grafts was 0.1% (range 0.01% – 13%). 6 patients who had measurable graft contamination became molecularly negative in blood and BM within 12 months after ASCT. Increasing fractions of BCL2/JH positive blood and BM cells reliably predicted morphologic and clinical relapse. Correspondingly, the 3 patients free of disease progression have sustained very low levels of molecular evidence of FL. In one illustrative case, a patient had a long-term low-level persistence of tumour cells in BM and blood with no clinical symptoms for 70 months post-ASCT. At 76 months there was a 10-fold increase in the quantity of PCR product in both BM and blood. Radiological evidence of relapse was observed 3 months later. The patient underwent spontaneous disease regression, which was paralleled by a 10-fold decrease in PCR product quantity at 82 months.Conclusions: Our simplified method of detection using quantitative PCR yields reliable measurements of graft contamination and MRD post ASCT, which may be useful in predicting patient relapse.

Once Daily Ganciclovir (ODG) as Initial Pre-Emptive Therapy (PT) Delayed until Threshold Viral Load ≥10,000 Copies/ml: A Safe and Effective Strategy for Post-Allogeneic Stem Cell Transplant (ASCT) Patients.

CMV infection is a major cause of morbidity and mortality in patients who have undergone ASCT. We previously evaluated the efficacy of ODG (5mg/kg/day) for 21 days as pre-emptive treatment for CMV viremia and found it to be effective and better tolerated than twice daily doses. We now report data evaluating ODG and PT using a quantitative CMV PCR strategy. At our institution, the detection limit of whole blood CMV PCR (WBP) is 200 copies/ml and the lower limit of quantitation 2000 copies/ml. No criteria for a standard treatment threshold currently exist for quantitative CMV PCR in plasma or whole blood. We elected to initiate treatment with ODG using a threshold WBP ≥10,000 copies/ml in clinically stable patients. Dose escalation was permitted for increasing WBP on ODG treatment. From 4/03 to 3/04, 98 patients underwent ASCT (44 related donors and 54 unrelated donors). 69/98 patients were at risk for CMV reactivation (donor/recipient CMV seropositive). Median follow-up was 318 (120–478) days post transplant. 48/69 (69.6%) patients had 1 or more episodes of CMV viremia (WBP >200 copies/ml). In 5/48 (10.4%) patients the WBP remained <10,000 copies/ml. All 5 patients cleared their viremia without treatment. 43/69 (62.3%) patients developed WBP ≥10,000 (11,324–53,000) copies/ml. 15/43 (34.9%) patients initiated treatment with BID ganciclovir (5mg/kg/BID) or foscarnet at the discretion of the treating physician. Most of these patients were acutely ill at the time of initial viremia. Two of these patients developed CMV pneumonitis which contributed to their deaths. 28/43 (65.1%) patients initiated treatment with ODG. Time to onset of viremia was a mean of 37.3 (19–62) days (>200 copies/ml) and 51.7 (27–196) days (≥10,000 copies/ml) post transplant. 10/28 patients increased ganciclovir to 5mg/kg/BID a mean of 12 (4–19) days after initiation of therapy due to increasing WBP (30,200–231,000 copies/ml). One patient developed neutropenia and was changed to foscarnet. In patients for whom WBP were available for the time points indicated, time to clearance of viremia (≤2000 copies/ml) for the 28 patients was 1/21 (5%) week 1, 8/25 (32%) week 2, 14/26 (54%) week 3, 22/27 (82%) week 4 and 26/28 (93%) week 5. Two patients did not clear their viremia at 5 weeks. One developed CMV colitis which was successfully treated. 17/28 patients remained on ODG for the 21 day treatment period. Time to clearance of viremia in this group was 1/10 (10%) week 1, 8/14 (57%) week 2, 12/15 (80%) week 3, 15/16 (94%) week 4, and 17/17 (100%) week 5. Recurrent viremia (WBP ≥10,000 copies/ml) occurred in 12/28 (43%) patients a mean of 109 (54–247) days post transplant. 2/28 (7%) patients developed CMV disease (colitis), 1 during the initial episode of viremia and 1 during a recurrence. Both were successfully treated. There were no deaths due to CMV disease in patients initiating therapy with ODG. Conclusion: Delaying treatment with ODG as initial PT until WBP ≥10,000 copies/ml is a safe and effective treatment strategy for CMV viremia post ASCT. This strategy reduces over treatment of patients and neutropenia.