High-dose Therapy With Autologous Stem Cell Transplantation Research Articles

Total late effect burden in long-term lymphoma survivors after high-dose therapy with autologous stem-cell transplant and its effect on health-related quality of life.

Lymphoma survivors after high-dose therapy with autologous stem-cell transplant (HDT-ASCT) are at risk of several late effects, which might impair their health-related quality of life (HRQoL). We assessed the total late effect burden in this population, and how it affects HRQoL. All lymphoma survivors treated with HDT-ASCT as adults in Norway between 1987 and 2008 were identified, and 271 (68%) attended both a comprehensive clinical assessment and completed a questionnaire. Severity of 45 conditions in 12 organ-system categories were graded as mild, moderate, severe or life-threatening, according to a modified version of CTCAEv4.03. At a median of 8 years after HDT-ASCT, 98% of survivors had at least one moderate or more severe late effect and 56% had severe or life-threatening late effects. Fourteen percent had low, 39% medium and 47% high late effect burden, defined as having moderate or more severe late effects in 0-1, 2-3 and >3 organsystems, respectively. Female sex, increasing age, B-symptoms at diagnosis and >1 treatment line prior to HDT-ASCT were independently associated with having high late effect burden. The survivors had significantly poorer physical and mental HRQoL assessed by the Short Form-36 compared to age- and sex-matched controls. The prevalence of poor physical and mental HRQoL increased with higher late effect burden (both P<0.001), and the low burden group had better physical HRQoL than controls (P<0.001). In conclusion, lymphoma survivors after HDT-ASCT have impaired HRQoL, seemingly driven by a high late effect burden. This highlights the importance of prevention, regular assessments for early detection and treatment of late effects and modifiable risk factors.

Lifestyle behavior among lymphoma survivors after high-dose therapy with autologous hematopoietic stem cell transplantation, assessed by patient-reported outcomes

Introduction: High-dose therapy with autologous stem cell transplantation (HD-ASCT) is associated with an increased risk of late effects. Our aim was to assess lifestyle behavior and factors associated with unhealthy lifestyle among HD-ASCT-treated lymphoma survivors (HD-ASCT-LS).Materials and methods: We conducted a national cross-sectional study of HD-ASCT-LS treated during 1987–2008. Among 399 eligible participants, 312 (78%) completed patient-reported outcome measures (PROMs) on lifestyle behavior (physical activity, overweight, smoking and alcohol consumption), chronic fatigue (CF) and somatic and mental illness. We assessed lifestyle according to WHO recommendations. Multivariable logistic regression models were used to study associations between variables. A comparison to the general population was performed.Results: Mean age at survey was 54.6 years, 60% were men, 55% sedentary, 55% overweight, 18% smokers and 5% had unhealthy alcohol consumption. Being sedentary was positively associated with older age, low household income, CF and higher somatic burden (≥4 self-reported somatic conditions). Overweight was positively associated with male gender and negatively associated with increased number of chemotherapy regimens prior to HD-ASCT. Current smoking was positively associated with living alone and CF, and negatively associated with older age. Male gender, CF and higher somatic burden increased the risk of an unhealthier lifestyle whereas the increased number of chemotherapy regimens prior to HD-ASCT decreased the risk. HD-ASCT-LS were significantly less sedentary, less overweight, and had a lower likelihood of smoking than the controls.Discussion: Assessed by PROMs, unhealthy habits were frequent among HD-ASCT-LS and associated with comorbidity. Nevertheless, compared with controls significantly more HD-ASCT-LS met lifestyle recommendations. These results indicate that the HD-ASCT-LS may consist of two groups, the adhering group with less comorbidity and the non-adhering group with more comorbidity. Our findings illustrate the necessity of recommendations and support for improving health-related behavior in cancer survivorship plans in order to empower survivors in their life beyond cancer.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

The Impact of Upfront Autologous Transplant on the Survival of Adult Patients with ALCL and PTCL-NOS According to Their ALK, DUSP22 and TP63 Gene Rearrangement Status - a Joined Nordic Lymphoma Group and Mayo Clinic Analysis

Introduction: Recent results from two independent patient series have shown that chromosomal rearrangements of DUSP22 (DUSP22r+) and TP63 (TP63r+) can predict outcome in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) with morphologic features resembling ALK-ALCL (Parilla-Castellar E, Blood 2014; Pedersen MB, Blood 2017). While DUSP22r+ is predictive for excellent survival similar to that of ALK+ALCL after CHOP/CHOP-like therapy, the rarely occurring TP63r+ is associated with an aggressive clinical behavior and poor outcome. The largest subgroup, i.e. patients with neither ALK nor DUSP22 nor TP63 rearrangements (triple negative), show a 5 year (yr) overall survival (OS) intermediate between that of ALK-/DUSP22r+ and ALK-/TP63r+ patients.The aim of the present study was to assess the impact of upfront high-dose therapy with autologous stem cell transplant (HDT/ASCT) on outcome in adult ALCL and PTCL-NOS patients according to their ALK, DUSP22 and TP63 status. The survival results from the two published series were pooled with those of a Nordic Lymphoma Group trial, the NLG-T-01 (d'Amore et al, JCO 2012), where patients were treated with 1st line CHOEP/CHOP followed, in chemosensitive cases, by upfront HDT/ASCT.Methods: Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation of DUSP22 and TP63 rearrangements was performed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Three independent patient cohorts were included: (i) one from Mayo Clinic consisting of 31 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 25; TP63r+: 6); (ii) one from Denmark consisting of 93 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 90; TP63r+: 3); and one from the NLG-T-01 trial consisting of 46 ALK-ALCL and PTCL-NOS (triple negative: 37; TP63r+: 1; DUSP22r+: 8), leading to a total study population of 170 patients. ALK+ ALCL was not included in the analysis, since no patients with this histology entered the NLG-T-01 trial. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional models for hazard rate ratios (HR). Significant differences were defined as P <0.05.Results: The eight DUSP22r+ patients (7 ALK-ALCL and 1 PTCL-NOS) from NLG-T-01 had a 5-yr OS of 83%, (95%CI 27-97), similar to that reported for DUSP22r+ in the Mayo and Danish cohorts (90% and 80%, respectively). No lymphoma-related events were observed in this subset. The only event was a septic death due to HDT-induced cytopenias in a patient who was in complete remission (CR). Among the 162 patients with DUSP22r-, ALK-ALCL and PTCL-NOS, those consolidated with HDT/ASCT (n=47) had a significantly better outcome (5-yr OS: 45%) than those treated with induction chemotherapy alone (5-yr OS: 30%) (n=115) (P=0.01). The patients in the HDT/ASCT group were younger (P<0.001) and had more advanced stage disease (P=0.002). The improvement in OS persisted when the analysis was limited to transplant eligible patients and adjusted for age and stage (HR 0.52 95%CI 29-91, P=0.023) or International Prognostic Index (IPI) groups (HR 0.49, 95%CI 20-82, P=0.006). Of the 10 TP63r+ patients found within the pooled cohort, 6 were transplant eligible. Of these, 5 were not transplanted (intention-to-treat) while one was (Nordic trial). The latter patient achieved a still ongoing long-term CR, while all others died of lymphoma progression.Conclusion: In ALK-ALCL and PTCL-NOS patients from the NLG-T-01 trial, DUSP22r+ was associated with a very good outcome, similar to that seen in DUSP22r+ patients who had not undergone upfront autologous transplant. This observation supports the impression that upfront HDT/ASCT may not be of benefit in these patients. TP63r+ predicted poor outcome in non-transplanted patients. The impact of HDT/ASCT in the TP63r+ setting could not be adequately evaluated, since only one patient from the NLG-T-01 trial cohort was found to be TP63r+. Notably, this patient was the only survivor of the TP63r+ subset. For DUSP22r-, ALK-ALCL and PTCL-NOS patients taken as one group, those who received upfront HDT/ASCT had a superior survival compared to their age- and IPI-matched non-transplanted counterparts. DisclosuresEllin:ROCHE: Consultancy, Research Funding; CTI: Consultancy. Mannisto:Roche: Honoraria, Other: Travel expence; Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Toldbod:Takeda Pharma: Honoraria.

Obstructive and restrictive pulmonary dysfunction in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation

Background: Obstructive and restrictive dysfunction in long-term lymphoma survivors (LSs) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) has not been addressed systematically previously.Material and methods: LSs treated in Norway 1987–2008 with HDT-ASCT who performed spirometry, measurement of static lung volumes and echocardiography 2012–2014 at either Oslo or St. Olavs University Hospitals was eligible. Smoking data were recorded by questionnaire. Treatment data were collected from medical records or hospital databases. Factors associated with obstructive and restrictive impairments (dichotomous outcomes) were examined by Poisson regression. Linear regression with the margins post-estimation command was used to derive adjusted mean values of forced expiratory volume in 1 s (FEV1). We used the normative reference data recommended by the European Respiratory Society for calculating percent predicted values.Results: A total of 226 LSs were studied, of whom 11.5 and 5.8% had obstructive and restrictive impairment, respectively. For women and men, mean FEV1 was 2.31 and 3.34 l corresponding to 11.4%- and 11.1%-points below that predicted from norms, respectively. In multivariable regression analyses, cumulative doxorubicin dose (400–775 mg/m2) and current smoking were associated with increased risk of obstructive impairment, and chest RT (>13–66 Gy) was associated with increased risk of restrictive impairment. Currently smoking LSs within the highest doxorubicin category (400–775 mg/m2), had the lowest adjusted mean FEV1.Conclusions: Despite intensive cancer treatment, our analysis showed modest reductions in obstructive parameters among long-term LSs after HDT-ASCT compared to normative reference data. To limit obstructive impairments in LSs after HDT-ASCT, we suggest that targeted smoking-cessation advice is directed towards patients who have received high cumulative doses of doxorubicin.

Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation

Background: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors.Material and methods: Eligible lymphoma survivors were aged ≥18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores ≥−1, between −1 and −2, and ≤−2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (≥−1), osteopenia (between −1 and −2.5), and osteoporosis (≤−2.5).Results: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <−1 and >−2, while 8% and 6% had Z-scores ≤−2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively.Conclusion: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT.

A national study on conditional survival, excess mortality and second cancer after high dose therapy with autologous stem cell transplantation for non-Hodgkin lymphoma.

This national population-based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) for non-Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18years treated with HDT-ASCT for NHL in Norway between 1987 and 2008 were included (n=578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5-, 10- and 20-year overall survival was 61% (95% confidence interval [CI] 56-64%), 52% (95%CI 48-56%) and 45% (95%CI 40-50%), respectively. The 5-year survival conditional on having survived 2, 5 and 10years after HDT-ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0-13·9), 4·9 (95%CI 4·1-5·9), 2·4 (95%CI 1·8-3·2) and 1·0 (95%CI 0·6-1·8) for the entire cohort and for patients having survived 2, 5 and 10years after HDT-ASCT respectively. Of the 281 deaths observed, 77% were relapse-related. Treatment-related mortality was 3·6%. The 10-year cumulative incidence of second malignancies was 7·9% and standardized incidence ratio was 2·0 (95%CI 1·5-2·6). NHL patients treated with HDT-ASCT were at increased risk of second cancer and premature death. The mortality was still elevated at 5years, but after 10years mortality equalled that of the general population.

High Dose Therapy with Autologous Stem Cell Transplantation (HDT/ASCT) Support in Follicular Lymphoma (FL) a Very Long Follow-up Analysis of 640 Patients of Geltamo Spanish Group Suggests That FL Might be Cured, Even in High-Risk Patients

Background: Patients with high-risk FL intensified with HDT/ASCT may achieve prolonged remissions. The best timing for the procedure remains controversial. Patients who are transplanted in first response show a major Progression Free Survival (PFS) and Event Free Survival (EFS) advantage compared to those treated with conventional chemotherapy. Nevertheless, no randomized studies have yet shown an overall survival (OS) benefit. Populational-based and very long-term retrospective analysis are indispensable tools to assess the actual impact on outcome of therapeutic interventions in FL. With this assumption we performed a retrospective analysis in FL patients undergoing HDT/ASCT intensification included in the GELTAMO Spanish Group Registry.Objectives: The overall outcome as well as the clinical evolution according to the disease status at transplant, to the Follicular Lymphoma International Prognostic Index (FLIPI and FLIPI II) and to the previous exposure to Rituximab.Series characteristics: Six hundred and sixty six patients with FL (mean age 47 years, male 49%) undergoing HDT/ASCT between 1989 and 2007 were reported to the GELTAMO registry. Patients with histological transformation at the time of HDT/ASCT, those undergoing a 2nd transplant and those with a follow-up of less than 7 years were excluded. Thus, 640 patients were included in the analysis. Median follow-up was 12.2 years from HDT/ASCT and 14.2 years from diagnosis. Follow-up from HDT/ASCT was over 16 years for 153 patients (3rd quartile). The median time from diagnosis to HDT/ASCT was 1.8 years. Two hundred and forty-seven patients (38%) never achieved a complete remission (CR) before HDT/ASCT. Two hundred patients (31%) received HDT/ASCT after achievement of first CR (CR1), 43% of them requiring more than one chemotherapy line to achieve CR1; 26% in 2nd CR, 5% in 3rd CR, 21% in 1st partial response (PR), 12% in chemosensitive recurrence, and 5% with active disease. Of the 321 patients assessable for the FLIPI, 33% had a low-risk (LR), 36% an intermediate-risk (IR), and 45% a high-risk (HR) score; and of the 305 patients assessable for the FLIPI II, 22% had a LR, 38% an IR and 40% a HR. Of the 127 patients in CR1 assessable for the FLIPI, 28% had a LR, 40% an IR, and 32% a HR; of the 115 patient assessable for FLIPI II, 14% had a LR, 46% an IR, and 40 % a HR. One third of patients received Rituximab prior to transplant.Results: Median PFS and OS were 9.4 and 21.3 years, respectively. Patients transplanted in CR1 achieved significantly better final PFS (68%) and OS (73%), than those transplanted in 2nd CR (median PFS 110 months (mo.) and final OS 58%; P <.0005) and the latter ones better than those transplanted in 1st PR (PFS median PFS 31 mo. and median OS 118 mo.; P < .0005) (figure 1). Neither FLIPI1 nor FLIPI2 reached statistical significance in patients transplanted in CR1 (P= .5 and P= .2 for PFS and OS, FLIPI 1 comparisons; P= .47 and P= .1 for PFS and OS, FLIPI 2 comparisons, respectively). Although in the global series patients who received Rituximab prior to HDT/ASCT had a better prognosis than those who did not (median PFS not reached vs median PFS 92 mo, respectively, P= .0005; median OS not reached vs median PFS 246 mo, respectively, P= .0012), treatment with Rituximab has no prognostic impact in cases transplanted in CR1. Only 6 patients died beyond 10 years of follow-up, (1 disease progression, 3 second malignancies, 2 unrelated causes). The accumulated incidence of second malignancies of the global series was 12%. A plateau was observed in the PFS and OS curves for patients transplanted in CR1 beyond 15.9 years from transplantation (figure 1).Conclusions: To the best of our knowledge there is no study on the therapeutic impact in the evolution of LF offering such a long follow-up. HDT/ASCT is a good option of consolidation for those patients who achieve a good quality of response with chemotherapy. The finding of a plateau beyond 15.9 years for patients transplanted in first remission suggests that a significant number of patients from this group may never relapse and could be cured, even those with poor initial features. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis

Oral mucositis is a major cause of morbidity in high-dose therapy/autologous stem cell transplantation (HDT/ASCT), where microbial colonization has an important pathological implication. In this study, we evaluated the impact of miconazole mucoadhesive buccal tablet (MBT) on mucositis-related complications. During two consecutive 34-month periods, patients treated with HDT/ASCT in our hematology department received either miconazole MBT (60 patients) or conventional oral amphotericin B suspensions three times a day (44 patients) in order to prevent or decrease chemotherapy-induced mucositis. The use of miconazole MBT is associated with less infectious complications as indicated by shorter antibiotic use (7.8 vs. 12.3 days; p < 0.0001), shorter intravenous antifungal use (1.4 vs. 3.6 days; p = 0.02), and a trend towards less yeast contamination in stool samples. Less patients required any analgesic drugs during hospitalization in the miconazole MBT group (18 vs. 7 %; p = 0.09). Indirect indicators of chemotherapy-induced mucositis (duration of hospitalization, morphine use) were in favor of miconazole MBT in patients with multiple myeloma (MM) but not for those with lymphoma. This study suggests that miconazole MBT provides a valid alternative to oral amphotericin B suspensions in regards to mucositis-related complications. A prospective and randomized study is warranted to establish the definite role of miconazole MBT.

Optimizing outcomes for patients with newly diagnosed multiple myeloma eligible for transplantation.

High-dose therapy with autologous stem cell transplantation (HDT-ASCT) has been considered to be the standard frontline treatment for younger, fit patients with multiple myeloma (MM) since the 1990s. Efforts continue to optimize the use of HDT-ASCT with the aim of improving outcomes. One strategy has been the incorporation of novel agents (thalidomide, lenalidomide and bortezomib) in the pre-transplantation setting as an induction therapy or in the post-transplantation setting as a consolidation or maintenance therapy. Given their high response rates, three-drug induction therapy regimens (for example, bortezomib-thalidomide-dexamethasone, lenalidomide-bortezomib-dexamethasone and cyclophosphamide-bortezomib-dexamethasone) are now the standard of care. Thalidomide and bortezomib are well suited for consolidation therapy, and regimens using these agents can improve the depth of response following HDT-ASCT. Lenalidomide is particularly well suited for long-term maintenance therapy following HDT-ASCT, and initial results are promising and have shown improvements in disease outcomes such as progression-free survival and overall survival in some cases, although a low incidence of second primary malignancies have been observed. Further studies are needed to determine the optimal regimen and duration of induction therapy, the impact of maintenance on overall survival and the safety of long-term treatment. Many of the studies currently underway in MM will help address these aspects.

Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma

OPINION STATEMENT: The standard front-line treatment of Diffuse Large B-Cell Lymphoma (DLBCL) remains Rituximab combined with multi-agent cytotoxic chemotherapy. In spite of high response rates to this therapy, relapsed/refractory disease is observed in up to 40% of patients. It is our opinion that additional chemoimmunotherapy, followed by high-dose therapy with autologous stem cell transplant (HDT-ASCT) for responsive disease, is the optimal therapy for these patients. However, many patients cannot tolerate HDT-ASCT, or have relapsed/refractory disease in spite of it. These patients have a poor overall prognosis, and there is no clear consensus as to how these patients should be treated. Over the past decade, significant advances have been made in the understanding of the molecular genesis and subtyping of DLBCL, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit. Examples include Bcl-2, Bcl-6, cell surface markers, and myriad molecules in both the B-Cell receptor and PI3K/Akt/mTOR pathways. As agents targeting these molecules and pathways progress from preclinical models to early clinical trials, more is learned about what might predict for response to these agents, such as cell of origin classification, and/or expression of relevant molecular markers, as measured by immunohistochemistry or gene expression profiling. Both the successes and failures of these novel targeted agents promise to dramatically refine, improve, and individualize the classification and treatment of DLBCL. Therefore, it is our opinion that patients with relapsed/refractory DLBCL are an ideal population for clinical trials due to both the lack of standardized treatment, and the recent advancements in pathobiology and early-phase treatment options.

Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection

The purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting. From 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied. The prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3-5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient. Use of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM.

Survival of Patients Autografted for Chemosensitive Hodgkin Lymphoma After Failure of Upfront BEACOPP Escalated Versus ABVD-Like Regimens

Abstract 3098 Background.Upfront treatment for advanced Hodgkin lymphoma (HL) is a matter of debate. The wide difference in progression-free survival (PFS) or freedom from treatment failure observed between the intensified regimen escalated (esc) BEACOPP and other standard intensity schedules - such us ABVD, ABVD hybrids and BEACOPP baseline - is in contrast with a small difference in overall survival (OS) [NEJM 2011;365 :203 and JCO 2009;27 :4548]. This fact suggests that high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) can salvage more patients treated with standard intensity schedules than escBEACOPP treated patients. Methods.In order to better understand this subject we analyzed all Swiss cases of refractory/relapsed HL that received HDT/ASCT after failure of at least 4 cycles of upfront escBEACOPP (4 to 8 cycles), given alone or combined with other regimens (cases, n=22) and compared outcomes with a control group of 33 patients transplanted after failure of upfront ABVD (N=18), ABDV-based combinations (hybrids, N=7), BEACOPP baseline (N=5) or up to 3 cycles of escBEACOPP plus radiotherapy (N=3). The high-dose schedule used before transplant was BEAM for 51/55 patients and CBV in 1 case and 3 controls. Results.Controls and cases were statistically similar in terms of timing of transplant (median year 2006 vs 2007), age at transplant (median 33 vs 28 years), sex (males 64% vs 68%), HL subtype, Ann Arbor stage, international prognostic score, ESR (38 vs 59 mm/1h) and bulky presentation (35% vs 60%), but there were significantly more B-symptoms among escBEACOPP patients (77% vs 23%, p=0.007). Furthermore, chemosensitivity (94% vs 82%), timing of relapse after upfront treatment (0–3 months: 30% vs 22%, 3–12 months: 18% vs 23% and >12 months: 52% vs 55%), median number of CD34+ cells reinfused (4.11 vs 2.99 ×10*6/kg), and need for a second salvage (12% vs 27%) were not significantly different in the two groups.After a median post transplant follow up of 42.5 months, median PFS was 15.4 months for escBEACOPP, and was not reached for control cases (p=0.145). Two-years OS was 84% for controls (95% CI 65%-93%) and 72% for escBEACOPP (95% CI 45%-87%), while 5-years OS was 68% (95% CI 44%-84%) and 65% (95% CI 37%-83%) for controls and cases, respectively. Four of 33 controls (12%) and 3 of 22 (14%) upfront escBEACOPP cases received an allograft for relapsed HL after HDT/ASCT (p=NS). The incidence of severe (grade 3–4) anemia, thrombocytopenia, neutropenia, diarrhea, stomatitis and neutropenic fever was similar in the two groups. Regarding uncommon/unexpected toxicities of HDT/ASCT, one patient in the escBEACOPP group developed grade 4 encephalopathy, whilst in the control group we observed two cases of acute renal failure, one ARDS and one fatal stroke. One patient in the control group was diagnosed with a T-cell lymphoma after transplant (p=NS). Three t-MDS plus one t-AML were recorded among patients in the escBEACOPP group, with no cases of t-AML/t-MDS occurring among those treated with the less intensive approaches (p=0.023). Conclusion.In our series, overall survival of chemosensitive HL patients autografted after failure of either upfront escBEACOPP or standard intensity regimens is encouraging. HDT/ASCT consolidation of chemosensitive patients failing upfront escBEACOPP seems justified. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

First Interim Safety Analysis of a Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated by Autologous Hematopoietic Stem Cell Transplant,

Abstract 4110 Background:The ACT trial (ACT-1 and −2) tests the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP (A-CHOP-14) followed, in younger patients (ACT-1), by high-dose therapy with autologous stem cell transplant (HDT/ASCT) in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). To date, the trial has accrued a total of 131 patients (ACT-1 n=72; ACT-2 n=59). Here, we present the first planned interim safety analysis of the ACT-1 trial based on the first 51 randomized patients. Aims:The aim of the present analysis is to report on the feasibility of a dose-dense chemo-immunotherapy schedule combining ALZ and bi-weekly CHOP followed by HDT/ASCT in ‘de novo’ PTCL patients. Results:Results contain two data subsets corresponding to ALZ dose levels prior and subsequent to a dose-reduction amendment tapering ALZ dose from 360 mg (30 mg on days 1 and 2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively. Of the 51 randomized patients, 43 had a complete set of evaluable data and represent the background for the present set of results. Of these, 5 received the higher ALZ dose, 17 the lower and 21 belonged to the antibody-void control arm. Treatment arms were well balanced with regard to histological subtypes, IPI sub-groups, and single prognostic factors. Neither of the two treatment cohorts, and for the experimental one irrespective of ALZ dose level, showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 3–4 leucopenia and anemia were more frequent in ALZ-treated patients (71% vs 29% and 47% vs 14%, respectively), whereas no difference was seen in terms of thrombocytopenia (17% vs 18%). Non-hematological toxicity unrelated to infectious complications was similar in the two groups. At the higher ALZ dose level, two cases of systemic fungal infection were reported, of which one (verified as being aspergillosis) with fatal outcome in a patient with pre-existing type II diabetes and steroid-requiring chronic obstructive pulmonary disease. These two events prompted the ALZ dose-reduction amendment, which led to a significant drop in the number of serious adverse events (SAEs) for ALZ-treated patients (SAE/patient pre-amendment: 2.6, post-amendment: 0.76) to a level comparable with the control arm (SAE/patient pre-amendment: 0.67, post-amendment: 0.44). With regard to the types of infection (≥grade 2), there was a similar frequency in reported fungal infections between the two treatment cohorts, bacterial infections were more often reported in the standard treatment arm (55% vs 46%), while the opposite was observed for viral infections (29% vs. 35%). Among the latter, there were 8 cases of cytomegalovirus reactivation among ALZ-treated patients, of which only two were clinically symptomatic and regressed upon specific treatment. Conclusion:In conclusion, the early-on impression of a SAE decrease subsequent to the ALZ dose-reduction amendment (applied on both ACT-1 and ACT-2) has been further confirmed by a larger cohort of patients treated at the lower ALZ dose level. The number of adverse events in the two study arms is now fairly comparable and adds further useful information to the previous reports on feasibility of stem cell harvest (Blood 2010;116: 2395) and hematopoietic recovery (Ann Oncol 2011;22(s4): 476) in ‘de novo’ PTCL patients treated with a dose-dense ALZ-CHOP regimen followed by HDT/ASCT. Disclosures:Walewski:4SC AG: Consultancy. Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A new predictive model based on age, pretreatment LDH, and post-therapy PET-CT in patients with MCL treated with dose-intensive strategies.

8051 Background: The use of dose-intensive strategies (R-HyCVAD) and/or high dose therapy with autologous stem cell transplant (HDT/ASCT) in the1st-line setting in MCL has shown improvement in PFS ...

Incorporation of Bortezomib Into Frontline Treatment of Multiple Myeloma According to Risk Stratification Shifts the Most Significant Prognostic Indicator From Cytogenetics to the Quality of Induction Response

AbstractAbstract 3056 Introduction:Multiple myeloma (MM) is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several adverse features of MM, it has been incorporated into the induction algorithms of high-risk MM. We evaluate the survival data of MM patients managed in a single institution, overall, and with respect to treatment eras before (era 1) and after (era 2) the incorporation of bortezomib as frontline therapy for high-risk MM. Methods:From a comprehensive MM registry maintained in a tertiary institution, we study the survival data of 304 consecutive and previously untreated MM patients managed at our institution from 2000 to 2009. For induction therapy, transplant-eligible patients received.VAD chemotherapy from 2000 to 2004, and thalidomide/dexamethasone (thal/dex) combination from 2004 to 2009. Transplant-ineligible patients received VAD chemotherapy, thal/dex or melphalan/prednisolone (MP) combination from 2001 to 2004, and thal/dex or MP/thalidomide combination from 2004 to 2009. Patients < 65 years were eligible for high-dose therapy with autologous stem cell transplant (HDT/ASCT). Bortezomib became available for treatment of relapsed disease from 2004 and was incorporated into induction therapy in selected patients with high-risk MM from 2006. High-risk MM is defined by presence any adverse factors including stage III on the International Staging System (ISS), deletion 13, hypodiploidy, pseudo-diploidy or near-tetraploidy on metaphase karyotyping, or presence of deletion 17p, t(4;14) or t(14;16) on interphase florescence in-situ hybridization (FISH). As FISH was only available from 2004, the results of FISH will not be included in the survival analysis. Patient and disease characteristics, and survival data were evaluated overall, and with respect to treatment eras. Disease response was assessed by the IMWG criteria after induction treatment and after HDT/ASCT for transplant ineligible and eligible patients respectively.We applied multivariate Cox's regression modeling to determine what baseline parameters, along with the eventual induction response, significantly affected the OS in the respective eras. Results:The median age of all patients was 62 years. Overall, 35%, 40% and 25% of patients presented with ISS stages I, II and III respectively. Conventional karyotyping detected abnormalities in 49% (del 13 [17%], hypodiploidy [18%], hyperdiploidy [22%], pseudodiploidy [7%] and near tetradiploidy [2%]) of patients. Overall, the ISS, conventional cytogenetics, age (≤ or > 60 years), the presenting platelet count (≤ or > 140 × 109/L) and the induction response attained were discriminating of the overall survival (OS) (median= 5.2 yrs) on univariate analyses. Patients and disease characteristic and number of patients undergoing HDT/ASCT were comparable between the 2 eras. 33% of patients in era 1(N=182) were exposed to bortezomib predominantly in the relapse setting, while 52% (41% upfront, 59% during relapse) of patients were exposed to bortezomib (N=123) in era 2. Number of patients attaining ≥ very good partial response (VGPR) were significantly higher in era 2 compared with era 1 (48% vs 26%, p<0.001). The median OS of patients in era 1 and 2 were 5.1 and 6.0 respectively (P=0.06). On multivariate analysis stratified by era, the presence of an abnormal non-hyperdiploid karyotype was the most significant prognostic factor in predicting a worse outcome in era 1(median OS 2.7 years, hazard ratio 3.4, p=0.02), while the attainment of ≥VGPR emerged as the single most significant factor in predicting a favorable outcome in era 2 (median OS 8.1 years, hazard ratio 0.01, p<0.001). Conclusion:Our study suggests that bortezomib use in the frontline, rather than relapse setting may be better able to overcome the effects of adverse cytogenetics. Superseding the adverse effects of all other presenting clinical and laboratory parameters, the attainment of ≥VGPR emerged as the single most significant predictor of long-term survival in the era of novel therapy. Disclosures:No relevant conflicts of interest to declare.

Risk of Hepatitis B Virus (HBV) Reactivation and the Role of Anti-Viral Prophylaxis in Multiple Myeloma Patients with HBV Infection in the Era of Novel Therapies.

Abstract 3882Poster Board III-818 IntroductionPatients with hepatitis B virus (HBV) infection, defined by the presence of HBV surface antigen (HBsAg), have an increased risk of HBV reactivation when they are on immunosuppressive treatment for multiple myeloma (MM). Although there is no guideline for MM patients with HBV infection, current lymphoma guidelines do recommend that these patients should receive antiviral prophylaxis during and after chemotherapy. Of late, the advent of bortezomib in the management of MM has resulted in a high reported incidence of variecella-zoster reactivation. The risk of HBV reactivation in MM patients with HBV infection undergoing treatment has not been previously studied. As HBV infection is endemic in Asia, we sought to evaluate the prevalence of HBV infection in our patients, the incidence of its reactivation especially in patients receiving bortezomib and the role of anti-viral prophylaxis. MethodsPreviously untreated MM patients diagnosed from 2000-2008 who were tested for HBsAg in our institution were included. Hepatitis attributable to HBV reactivation was defined as an increase in HBV DNA levels of tenfold, or an absolute increase greater than105 copies/ml in the HBV DNA level. HBV infected patients were prospectively followed. 33% of all patients have been exposed to bortezomib, while 26% received high dose therapy with autologous stem cell transplantation (HDT/ASCT). Results243 untreated MM patients were identified. The prevalence of HBV infection is 5.8% (14/243). 6 (43%) HBV infected patients had detectable HBV DNA viral load (>3 log) at baseline. All 6 patients had normal baseline liver function tests and received lamivudine prophylaxis. All 14 HBV infected patients went on to receive systemic therapy for MM, with continual monitoring of HBV DNA viral load and liver enzymes for viral reactivation. 4 patients with undetectable HBV DNA load did not receive anti-viral prophylaxis. Of these 14 patients, 3 (21%) who had been on lamivudine prophylaxis had reactivation of the virus, with 1 dying from it, and 1 having emergence of a mutant viral strain. Two of them had no detectable viral load at presentation. Two patients reactivated 3 and 5 months after HDT/ASCT, while 1 reactivated immediately after a bortezomib/ doxil salvage regimen. ConclusionThe risk of HBV reactivation appeared to be commonest during the immune reconstitution phase after HDT/ASCT. Although the majority of patients with HBV infection and not receiving HDT/ASCT do not reactivate, the risk may not negligible when bortezomib is used (7%). Undetectable HBV DNA and the use of anti-viral prophylaxis do not appear to preclude reactivation. The optimal use of anti-viral prophylaxis, particularly if bortezomib is given, should be further evaluated. This is particularly relevant in the current era where bortezomib plays a dominant role in the treatment of MM, and especially in endemic regions where the incidence of HBV infection is high. Disclosures:No relevant conflicts of interest to declare.

Hemopoietic stem cell transplantation in T-cell malignancies: Who, when, and how?

Only in recent years has there been a specific focus on the treatment of T-cell lymphomas in general and peripheral T-cell lymphomas (PTCLs) in particular. An increasing number of PTCL-specific retrospective analyses have been reported, and the first data from PTCL-restricted prospective clinical trials have appeared more recently. In this context, the role of hemopoietic stem cell transplantation-primarily autologous but also allogeneic-has been investigated. High-dose therapy with autologous stem cell transplantation (HDT/ASCT) proved feasible in both relapsed/refractory and previously untreated PTCL. Overall results show a more favorable impact when HDT/ASCT is part of first-line therapy rather than salvage treatment. Reported outcomes have varied, often depending on the number of anaplastic large-cell lymphomas in the cohort. In addition, retrospective results usually focus on patients undergoing transplantation, whereas the fraction of patients with primary refractory or early relapsing disease is best described in the intention-to-treat analysis of prospective trials. This article reviews the most recent results of upfront HDT/ASCT consolidation in different subtypes of systemic PTCL. The data on allogeneic stem cell transplantation are more limited, but promising results have recently been reported in the setting of relapsed or primary refractory disease.

Relationship Between Depth of Response and Outcome in Multiple Myeloma

High-dose therapy with autologous stem-cell transplantation (HDT-ASCT) is now almost standard therapy for many patients with multiple myeloma, partly because of higher complete response (CR) rates. Some studies suggest that tandem transplantation gives superior results. The aim of this study was to determine whether the depth of the response to HDT-ASCT leads to an improvement in time to progression (TTP) and overall survival (OS). We hypothesized that patients with CR before HDT-ASCT (BCR) will have their disease burden reduced further and experience a longer TTP and perhaps OS. All patients who achieved BCR or CR after HDT-ASCT (ACR) were identified. The characteristics and long-term outcome of these patients were evaluated. We identified 14 patients with BCR and 103 patients with ACR who were treated in similar fashion. The patients have been followed for more than 6 years, and the median for OS has not been reached (60-month survival, 55% for BCR and 63% for ACR; P = .83). The median TTP was 43 months for BCR and 34 months for ACR (P = .39). The depth of the response in myeloma does not necessarily lead to an improvement in TTP and OS. Tumor dynamics considerations show that the yield from sequential cycles of chemotherapy decreases. Patients who achieve CR with the first transplant can be safely observed without jeopardizing OS.

Serum M‐spike and transplant outcome in patients with multiple myeloma

High dose therapy with autologous stem cell transplantation (HDT-ASCT) has prolonged survival in patients with multiple myeloma. Patients who achieve a complete response (CR) benefit the most from this form of therapy. Thus, achieving a CR is an important goal of therapy and it will be beneficial if the probability of achieving CR can be determined for any patient before transplant. Here we report that pretransplant monoclonal protein level (M-spike) was found to be an important predictor. Thus, we used knowledge of the rate of M-protein production by myeloma cells together with the clearance of the protein to estimate the pretransplant disease burden. We show that the pretransplant disease burden, based on the M-spike, is the only predictor for achieving CR. A simple function that describes this probability is presented. We also provide an estimate of the rate of tumor regrowth in patients who obtain a CR and in patients who only get a partial response with HDT-ASCT. The significant expansion of myeloma cells after HDT-ASCT is clearly evident. Clinical trials must be designed that take into account these kinetic aspects of the disease.