Treatment Of High-risk Disease Research Articles

P542: REAL WORLD OUTCOMES FOR PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA IN BRITISH COLUMBIA (BC): EXCELLENT OUTCOMES WITH LOW EARLY DEATH RATE AND HIGH OVERALL SURVIVAL IN A POPULATION BASED STUDY

Background: Acute promyelocytic leukaemia (APL) therapy has significantly improved with the use of All trans retinoic acid (ATRA) and Arsenic Trioxide (ATO) for low risk disease (Lo-Coco 2013). Treatment of high risk disease remains more challenging with a higher risk of early mortality & greater concern of relapse. All patients (pts) with APL in British Columbia, Canada are treated by the Leukemia/BMT Program at Vancouver General Hospital, Vancouver. Since 2014, all pts have received ATRA/ATO based therapy based on the Le-Coco study. Pts with high risk disease (WCC > 10 x 109/L at presentation) also receive a 3 day course of doxorubicin (60mg/m2) for induction only. Aims: We sought to review treatment outcomes since initiating these treatment protocols with emphasis on drug toxicities, dose modifications & management of high risk & elderly patients in order to describe real world outcomes. Methods: Ethics was approved by the board of the BCCA and UBC. Data was collected by chart reviews, hospital databases & collated on a central file. Demographics, risk stratification, treatment received, adverse events & survival was collected & analysis performed on Microsoft excel v16.57 & SPSS Statistics v28.0.1.1. Kaplan Meier curves were performed for PFS & OS, student t and chi squared tests were performed to assess differences between subgroups. Results: We identified 67 pts with APL during the study period. 40% were male 60% female, the median age was 61 yrs. (21-83yo). 36(54%) pts were > 60 yrs at diagnosis. The median duration of follow up was 2.9 yrs. All had molecular confirmation of disease. 16(24%) pts had high risk disease at diagnosis. At time of censor overall survival was 97% and PFS 94%. 55(82%) pts had a documented toxicity. Common toxicities included differentiation syndrome (DS) in 27(40%) pts, hepatotoxicity 17 (25%), QTc prolongation 13(19%) & neurological effects 9 (13%). Infections were documented in 40(59%) pts including bacterial infections in 25 patients (37%), culture negative febrile neutropenia in 12 (20%), viral infections in 5 (7%) & fungal infections in 1 (1.5%). Clinically significant bleeding was documented in 10 (15%) of patients, 5 of which were CNS/retinal bleeds. DS was more common in high risk disease though this difference was not statistically significant (p=0.365). 8(30%) pts with DS needed ICU admission. There were 2 early deaths, in the cohort, both in pts > 75 yo with high risk disease due to multi-organ failure and bleeding within 5 days of presentation. Dose modifications were assessed in 64 pts (2 deaths & one lost to follow up). 37 (58%) were described as having had a dose modification. 13 (20%) had a reduction in treatment dose, 16(25%) had doses/days of drug omitted. 6(9%) had reductions in dose and omissions. The most common reasons for dose modifications were DS 12(19%), QTc prolongation 10 (15%) & hepatotoxicity 8 (12%). Pts over 60yo were more likely to have a dose modification than pts below 60yo (73% vs 43% p = 0.014). 65 pts diagnosed achieved morphological remission & 64 a molecular remission at the end of planned therapy. 2 relapses occurred in our cohort, 1 had a concomitant cytogenetic abnormality incorporating a Tp53 deletion. The second initially received ATRA only induction due to age & comorbidity. Summary/Conclusion: This real world, population based data for patients with APL in BC confirms high response rates, survival and relatively low early death rate and acceptable toxicity even in older patients with high risk disease and comorbidities. In our cohort appropriate dose modifications did not impact remission or relapse rates.

The role of robot-assisted radical prostatectomy in high-risk organ-confined prostate cancer.

The traditional open retropubic radical prostatectomy has an established role in the treatment of prostate cancer. However, it is well known to be morbid procedure with high complication rate. This bad reputation prevented utilizing it on a large scale for high risk prostate cancer. Utilizing the da Vinci® to preform radical prostatectomy decreased the morbidity of the procedure. Since the introduction of robotic prostatectomy, there have been hot debates on its role in the treatment of high risk disease. In this article we reviewed the current evidence on utilizing the surgical system in treating high risk organ confined prostate cancer.

Challenges and Future Directions in the Detection and Treatment of Retinopathy of Prematurity

Multicenter studies addressing screening and intervention for retinopathy of prematurity (ROP) inform the management guidelines jointly recommended by American pediatric and ophthalmology academies. Current research focuses on improvements in the identification of ROP and in the treatment of high-risk disease. The development of digital image technology may address various challenges in the diagnosis of ROP, including availability of pediatric ophthalmologic expertise, interobserver variation in diagnosis, and inherent limitations in visual diagnosis. Improved clinical prediction models based on nonophthalmologic data may complement examination-based ROP diagnosis. Alternatives to retinal ablation therapy are being studied to decrease the associated morbidities of such therapy.

Abstract 2477: An orally bioavailable and selective histone deacetylase (HDAC) 1 & 2 inhibitor enhances retinoic acid mediated differentiation of neuroblastoma

Abstract INTRODUCTION: Neuroblastoma (NB) is an extra-cranial solid cancer and is among the most common cancers in infants less than 1 year of age, with 650 new cases each year in the United States. Half of the children with NB have high risk disease and 20-50% of those will fail to respond adequately to current therapies, illustrating an urgent unmet medical need. Current treatment for high-risk disease is aggressive, including chemotherapy, surgery, radiation with stem cell transplant, anti-GD2/cytokine immunotherapy and retinoic acid (RA) treatment. RA is a pro-differentiation agent that slows growth and promotes cell death. A gene expression pattern associated with RA-induced NB differentiation was identified, and chemical inhibition of HDAC1/2 was shown to induce a similar expression pattern. METHODS: In this work, we examine the activity of an orally bioavailable HDAC1/2 inhibitor (HDAC1/2i) on NB cell differentiation, proliferation and apoptosis. RA combined with HDAC1/2i enhances gene expression patterns associated with differentiation, slows cellular proliferation and more rapidly induces dendrite formation than RA can achieve alone. The mechanisms leading to the differentiated phenotype were examined by RT-PCR, gene expression microarray and retinoic acid receptor (RAR) chromatin immunoprecipitation followed by high-througput sequening (ChIP-Seq). RESULTS: HDAC1/2i and RA together caused increased localization of the RAR to its own RARα and RARβ promoter regions, and increased in RAR mRNA and protein relative to the RA treatment condition alone. Additionally, expression of Cyp26, an enzyme responsible for clearing intercellular RA, was reduced in the combination setting. Gene set enrichment analysis of the microarray data comparing the combination setting against RA as a single agent suggested that the addition of HDAC1/2i enhanced apoptotic pathways and decreased E2F driven cell cycle signaling. We confirmed enhanced apoptosis in the combination setting by measuring caspase 3 and PARP cleavage. Consistent with this finding, we observed reduced proliferation, increased sub-G1 cell frequency in cell cycle assays and ablation of emergent RA-resistant NB colonies after combination treatment. Further, combination treatment reduced the E2F-activators CDK4 and CDK6 at the protein level while the CDK inhibitor, p21, was dramatically increased. Hypo-phosphorylation of retinoblastoma protein, directly linked to E2F complex inactivation, was also observed and consistent with reduced proliferation and the decreased frequency of S-phase cells observed in EDU incorporation assays. Xenograft models of NB with RA and HDAC1/2i are in progress, as are HDAC1, HDAC2, acetylated histone H3K9 ChIP-seq experiments, and will be discussed. Taken together, these findings support a role for selective HDAC1/2i in combination with RA for the treatment of patients with high risk NB. Citation Format: David L. Tamang, Pengyu Huang, Olga Golonzhka, Jeffrey R. Shearstone, Steven N. Quayle, Simon S. Jones, Min Yang. An orally bioavailable and selective histone deacetylase (HDAC) 1 & 2 inhibitor enhances retinoic acid mediated differentiation of neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2477.

Abstract A136: A novel, orally bioavailable and selective histone deacetylase (HDAC) 1 & 2 inhibitor enhances retinoic acid mediated differentiation of neuroblastoma

Abstract Neuroblastoma (NB) is an extra-cranial solid cancer arising from the neural crest and is among the most common cancers in infants less than 1 year of age (Park, JR et al., 2008). Approximately one child per 100,000 is diagnosed with NB, resulting in 650 new cases each year in the United States. Half of the children with NB have high risk disease and 20-50% of those will fail to respond adequately to current therapies, illustrating a clear unmet medical need. Current treatment for high-risk disease is aggressive, including chemotherapy, surgery, radiation with stem cell transplant, anti-GD2/cytokine immunotherapy and retinoic acid (RA) (Yang, RK et. al., 2010; Cheung, NK et. al., 2012). RA is a pro-differentiation agent that slows growth and promotes cell death. A gene expression pattern associated with RA-induced NB differentiation was identified (Hahn, CK et. al., 2008; Frumm, SM et. al., 2013), and inhibition of HDAC1/2 was shown to induce a similar expression pattern. In this work, we examine the activity of an orally bioavailable HDAC1/2 inhibitor (HDAC1/2i) on NB cell differentiation, proliferation and apoptosis. RA combined with HDAC1/2i enhances gene expression patterns associated with differentiation, slows cellular proliferation and more rapidly induces dendrite formation than RA can achieve alone. The mechanisms leading to the differentiated phenotype were examined by microarray and retinoic acid receptor (RAR) ChIP-seq. HDAC1/2i and RA together caused increased localization of the RAR to its own RARa and RARß promoter regions, and an increase in mRNA and protein relative to the RA treatment condition alone. Additionally, expression of Cyp26a1/b1, enzymes responsible for clearing intercellular RA, were reduced in the combination setting. Gene set enrichment analysis of the microarray data comparing the combination setting against RA as a single agent suggested that the addition of HDAC1/2i was enhancing apoptotic pathways and decreasing E2F driven cell cycle signaling. In further experiments, we confirmed enhanced apoptosis in the combination setting by measuring caspase 3 and PARP cleavage, which is consistent with reduced proliferation, increased sub-G1 cell frequency in cell cycle assays and ablation of emergent RA-resistant NB colonies. Further, the E2F-activators, CDK4 and CDK6, were reduced at the protein level in the combination setting while the CDK inhibitor, p21, was dramatically increased. Hypo-phosphorylation of retinoblastoma protein, directly linked to E2F complex inactivation, was also observed and consistent with reduced proliferation and the decreased frequency of S-phase cells observed in EDU incorporation assays. Xenograft models of NB with RA and HDAC1/2i are in progress and will be discussed. Taken together, these findings support a role for selective HDAC1/2i in combination with RA for the treatment of patients with high risk NB. Citation Format: David L. Tamang, Pengyu Haung, Olga Golonzhka, Jeff Shearstone, Steven N. Quayle, Simon S. Jones, Min Yang. A novel, orally bioavailable and selective histone deacetylase (HDAC) 1 & 2 inhibitor enhances retinoic acid mediated differentiation of neuroblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A136.

Abstract 2196: Novel and selective histone deacetylase (HDAC) 1 & 2 inhibitors enhance differentiation of neuroblastoma cells in combination with retinoic acid

Abstract Neuroblastoma is an extra-cranial solid cancer arising from the neural crest and is among the most common cancers in infants less than 1 year of age (Park, JR et al., 2008). Approximately one child per 100,000 is diagnosed with neuroblastoma, resulting in 650 new cases each year in the United States. Half of the children with neuroblastoma have high risk disease and 20% - 50% of those children will fail to respond adequately to current therapies, illustrating a clear unmet medical need. Current treatment for high-risk disease is aggressive, including chemotherapy, surgery, radiation with stem cell transplant, anti-GD2/cytokine immunotherapy and retinoic acid (Yang, RK et. al., 2010; Cheung, NK et. al., 2012). Retinoic acid is a pro-differentiation agent that acts on neuroblastoma cells to slow growth and promote cell death. A gene expression pattern associated with retinoic acid induced neuroblastoma differentiation was recently identified (Hahn, CK et. al., 2008; Frumm, SM et. al., 2013), and it was further shown that inhibition of HDAC1/2 was able to induce a similar expression pattern. In this work, we demonstrate that next generation selective and orally bioavailable HDAC1/2 inhibitors can induce gene expression changes in neuroblastoma cells consistent with differentiation. The action of HDAC1/2 inhibitors potently enhances the retinoic acid differentiation effect at sub-optimal concentrations of retinoic acid or HDAC inhibitor, as well as with intermittent (pulse) HDAC1/2 inhibition. Retinoic acid alone and in combination with HDAC1/2 inhibitors is able to slow cell proliferation in long term growth assays and alter morphology in a manner consistent with differentiation. The observed enhancement of differentiation by selective HDAC1/2 inhibitors occurs at concentrations below that required for cell death as evidenced by viability assays and caspase 3/7 activation. Acute toxicity is induced by elevated concentrations of HDAC1/2 inhibitors, and synergy is observed in combination with retinoic acid. Ongoing studies exploring global gene expression changes, ChIP-seq examining retinoic acid receptor and HDAC1/2 chromatin binding, and activity of the selective HDAC1/2 inhibitor in combination with retinoic acid in animal models of neuroblastoma will be discussed. Taken together, these findings support a role for selective HDAC1/2 inhibitors in combination with retinoic acid for the treatment of patients with high risk neuroblastoma. Citation Format: David L. Tamang, Emily Lurier, Olga Golonzhka, Steven N. Quayle, Simon S. Jones, Min Yang. Novel and selective histone deacetylase (HDAC) 1 & 2 inhibitors enhance differentiation of neuroblastoma cells in combination with retinoic acid. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2015-2196

Current clinical presentation and treatment of localized prostate cancer in the United States.

116 Background: This year, the Surveillance, Epidemiology, and End Results (SEER) database released individual patient clinical Gleason score (GS) at the time of biopsy/transurethral resection of the prostate (TURP), which, along with the previously available clinical stage and prostate-specific antigen (PSA), allows a unique opportunity to study the clinical presentation and treatment selection of prostate cancer in the US. Methods: The SEER database was used to identify men diagnosed with localized prostate cancer in 2010 who were then assigned National Comprehensive Cancer Network (NCCN) risk group based on clinical factors at diagnosis. We determined sociodemographic factors associated with having high-risk disease and analyzed the impact of NCCN risk, along with sociodemographic factors, on local treatment selection. Results: A total of 42,403 men were identified of which 16,171 (38%) had low-risk, 16,990 (40%) had intermediate-risk, and 9,242 (22%) had high-risk disease. Older, non-white, and non-married patients living in counties with higher poverty rates, were most likely to be diagnosed with high-risk disease on multivariable analysis. Of the 38,634 men for whom prostate cancer was the first malignancy, 8,832 (23%) had no local treatment, 15,421 (40%) had prostatectomy, 13,855 (36%) had radiation treatment (including external beam radiation and/or brachytherapy), and 526 (1%) had another form of local tumor destruction (predominantly cryotherapy). In total, 29% of low-risk, 16% of intermediate-risk, and 25% of high-risk patients received no local treatment (p < 0.001). On multivariable analysis, older, non-white, and non-married patients living in counties with higher poverty rates who had low-risk disease, were least likely to receive local treatment. Conclusions: Our analysis provides information regarding the current clinical presentation and treatment of localized prostate cancer in the US. We note persistent disparities in the presentation and treatment of prostate cancer according to sociodemographic factors and potential under treatment of high-risk disease.

Stem Cell Transplant As an Immunomodulatory Tool for Children with Hematologic Malignancies

Allogeneic stem cell transplantation (alloHSCT) is the most common and effective form of immunotherapy used for treatment of pediatric leukemias. A combination of graft manipulation, donor selection, fine-tuning of conditioning regimens, and use of lower and novel forms of immunosuppression following transplant has maximized the tolerability of alloHSCT in children. This outcome has facilitated new advances in disease-specific transplant regimens that seek to amplify the antitumor effects of the allograft, while reducing transplant-related mortality. However, disease relapse remains the preeminent challenge to the success of transplantation as a modality for successful treatment of high-risk disease. Separating graft versus host disease (GVHD) from graft versus leukemia (GVL) remains the most significant obstacle to enhancing disease-free survival. However, with increased clarity and discrimination in the effector mechanisms responsible for GVHD and/or GVL in patients of all ages, a new wave of clinical trials has become feasible that harnesses GVL effects to treat patients with high-risk myeloid and lymphoid malignancies. Exciting progress is being made in the use of alloHSCT with donor lymphocyte infusions (DLIs) in almost all forms of pediatric hematologic malignancies. This advance sets the stage for the use of HSCT and/or DLI in conjunction with novel disease-specific post-transplant therapies using small molecule therapeutics, tumor vaccines, and novel antibody therapies.

Survival and toxicity following chemoradiation for carcinoma of the cervix: Impact of multiple phase treatment and shielding.

e15506 Background: Concurrent chemoradiation is standard therapy for cervical cancer. At University Hospital Birmingham standard primary treatment consists of concurrent cisplatin with external beam radiotherapy (EBRT) at 45–50.4Gy in 25–28 fractions with or without a single medium-dose rate brachytherapy insertion of 25–27Gy to point A. Chemoradiation is also used for the post-operative treatment of high risk disease, with brachytherapy used for vaginal margin involvement. Between January 1999 and October 2006 multiphase treatment (EBRT volume reduced beyond 45Gy) and increased shielding of bowel and sacrum were introduced. We set out to establish outcomes and significant (grade 3-4) late toxicity (SLT) during this period, and to assess the impact of multiphase treatment and shielding. Methods: Retrospective review of case notes and radiotherapy planning films was used to obtain patient characteristics, EBRT dose by phase, number of shielded areas, and data related to overall and disease-free survival, local and distant recurrence, and late toxicity. Survival and progression-free survival was analysed using the Kaplan–Meier method and Log-rank test. Differences in SLT rates between groups were analysed using the Chi-squared and Fisher’s Exact tests. Results: 175 patients of median age 45 (22-76) were treated radically between 1999 and 2006. 74% received primary chemoradiation whilst 26% had post-operative treatment. 3 year survival for stages I, II and III disease were 89%, 76% and 51% respectively, with 3 year overall survival of 73.7% (95% CI 65.9-79.9) and 3 year progression-free survival of 71.6% (95% CI 63.3-78.4). Local pelvic failure was 9% and remained stable throughout the study period. Overall SLT rate was 13%, with lower rates for post-operative treatment than primary chemoradiation (4%v 16%, p=0.03). However with single phase treatment SLT was 29% versus 12% following multiphase EBRT, and 16% when <2 areas were shielded versus 6% with ≥3 shielded areas (p=0.01). Conclusions: Shielding and multiphase treatment not only reduce dose to organs at risk but can also reduce late toxicity without compromise of local control or survival.

The selective VEGFR1‐3 inhibitor axitinib (AG‐013736) shows antitumor activity in human neuroblastoma xenografts

Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high-risk disease. Within the KidsCancerKinome project, we evaluated the new oral selective pan-VEGFR tyrosine kinase inhibitor axitinib (AG-013736) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR-N91 derived from a primary bone marrow metastasis. Axitinib reduced cell proliferation in a dose-dependent manner with IC(50) doses between 274 and >10,000 nmol/l. Oral treatment with 30 mg/kg BID for 2 weeks in advanced tumors yielded significant tumor growth delay, with a median time to reach five times initial tumor volume of 11.4 days compared to controls (p = 0.0006) and resulted in significant reduction in bioluminescence. Simultaneous inhibition of VEGFR downstream effector mTOR using rapamycin 20 mg/kg q2d×5 did not statistically enhance tumor growth delay compared to single agent activities. Axitinib downregulated VEGFR-2 phosphorylation resulting in significantly decreased microvessel density (MVD) and overall surface fraction of tumor vessels (OSFV) in all xenografts as measured by CD34 immunohistochemical staining (mean MVD ± SD and OSFV at 14 days 21.27 ± 10.03 in treated tumors vs. 48.79 ± 17.27 in controls and 0.56% vs. 1.29%; p = 0.0006, respectively). We further explored the effects of axitinib on circulating mature endothelial cells (CECs) and endothelial progenitor cells (CEPs) measured by flow cytometry. While only transient modification was observed for CECs, CEP counts were significantly reduced during and up to 14 days after end of treatment. Axitinib has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma.

Diagnostik und Therapie des nicht muskelinvasiven Harnblasenkarzinoms – State of the Art

Around 80 % of newly diagnosed bladder cancers are confined to the mucosa and staged as non-muscle-invasive bladder cancer (NMIBC) (Ta, T1, Cis). These tumours appear to segregate into different main molecular pathways with extremely variable prognoses. The standard treatment for NMIBC is transurethral tumour resection (TUR) with Re-TUR and adjuvant intravesical chemotherapy or intravesical immunotherapy in most cases. Several developments associated with diagnosis such as the usefulness of the new WHO grading classification, the benefit of photodynamic diagnosis (PDD) or narrow band imaging (NBI), as well as the clinical value of tumour markers are discussed. Therapy for NMIBC includes monopolar or bipolar TUR. Subsequent instillation therapy is given according to the risk stratification. Several promising new substances as well as device-assisted procedures such as thermochemotherapy or EMDA are discussed. The additional information gained by PDD obviously leads to a better diagnosis and treatment of all NMIBC. Routine IVU does not seem necessary. The value of diagnostic urine tests is still insufficiently defined. Several new aspects concerning prognostic markers are presented. While early chemotherapy instillation seems sufficient in low-risk tumours and BCG is the standard treatment for high-risk disease, the literature about treatment of intermediate risk tumors is still conflicting. Especially problematic is the case of recurrent disease after intravesical therapy in intermediate and high-risk patients. The question as to what has to be done in failure after BCG is discussed. Cystectomy is a safe option but other approaches are potential alternatives.

The role of adjuvant anthracyclines for breast cancer treatment: Can we use molecular predictors?

Anthracyclines have been widely used in the adjuvant treatment of breast cancer and are part of most adjuvant regimens for the treatment of high-risk disease. The 2000 Early Breast Cancer Trialists Collaborative Group overview of polychemotherapy in breast cancer demonstrated that anthracycline-based regimens are superior to non-anthracycline-based therapies in terms of disease-free and overall survival. However, recently, there has been controversy related to anthracycline based on retrospective analyses which showed that only patients with human epidermal growth factor receptor 2 (HER2)-amplified tumors benefited from anthracyclines. However, caution must be used in basing treatments on retrospective data. HER2 should not be the only target used when considering an anthracycline because there may be other suspected molecular predictors of response, such as topoisomerase II alpha (TOPO II α) gene aberrations (amplifications and deletions), TOPO II α protein overexpression, and DNA repair dysfunction, as well as others as yet undiscovered. Further, TOPO II α gene amplifications and gene deletions have been seen in HER2-negative tumors. This review argues against the use of HER2 as the sole target for predicting response to anthracyclines.

Pre-transplant 18FDG-PET predicts outcome in lymphoma patients treated with high-dose sequential chemotherapy followed by autologous stem cell transplantation

We evaluated the prognostic role of 18FDG-PET performed before ASCT in patients affected by lymphoma who underwent high-dose chemotherapy followed by ASCT as first-line treatment for high-risk disease or as second-line or more for relapsed or refractory disease. We retrospectively analyzed 53 consecutive patients, 14 with Hodgkin Lymphoma (HL) and 39 with non-Hodgkin Lymphoma (NHL), treated between February 1999 and October 2006 at our institution, who had a pre-ASCT FDG-PET (pPET) evaluation. Median age was 45 years (range: 18 – 69). After a median follow-up of 31 months (range: 8 – 91), 7 out of 16 pPET+ patients and 10 out of 37 pPET− patients experienced lymphoma relapse. The 5-year OS is 90% and 55% (p = 0.01) in patients with negative and positive pPET, respectively. In conclusion, a positive pPET indicates a poorer outcome after ASCT with respect to a negative pPET; this subset of patients should be considered candidate to more intensive or investigational approaches.