High-dose Therapy And Autologous Stem Cell Transplantation Research Articles

Consolidative Radio therapy in Place of Autologous Stem Cell Transplant in Patients with Low-Risk Relapsed/Refractory (R/R) Classic Hodgkin Lymphoma (cHL) Treated with Nivolumab plus Brentuximab Vedotin: CheckMate 744

Standard of care treatment for patients with relapsed and refractory classic Hodgkin lymphoma (RRHL) involves second line therapy followed by high dose therapy and autologous stem cell transplant (HDT/ASCT) and carries with it significant costs and toxicities to the patient. Some patients with RRHL may not require such intensive therapy, especially in the era of targeted chemotherapy and checkpoint inhibitors. CheckMate 744 (NCT02927769) evaluated a novel second-line therapy that omits HDT/ASCT by combining brentuximab vedotin (BV) and a nivolumab (N) followed by consolidative ISRT for low risk RRHL. Pts were aged 5-30 y and had one prior treatment without HDT/ASCT. Low-risk RRHL were those at relapse without B symptoms or extranodal disease, limited sites of relapse (≤4 sites of disease above the diaphragm or ≤3 sites above/below the diaphragm) AND with initial Stage IA, IIA with relapse <1 year if they received ≤3 cycles of chemotherapy and no RT OR Stage IA/B, IIA/B, IIIA ≥ 1 year. Patients received 4 cycles of N + BV induction. Patients with complete metabolic response (CMR) received an additional 2 cycles of N + BV before RT consolidation. Patients with suboptimal response received 2 cycles of BV + bendamustine intensification. Those patients achieving CMR proceeded to RT consolidation. RT was delivered to a dose of 30-30.6 Gy at 1.5-1.8 Gy/fraction to an ISRT volume. Among 28 pts treated, the median age (range) was 17 (6-27) years old and 64% of patients were aged < 18 y. Most (79%) pts had stage II disease at diagnosis and 82% had relapsed ≥ 12 months after first line treatment. Of 27 pts continuing in study after induction N + BV, 6 received bendamustine + BV intensification, and 92.9% achieved complete metabolic response. Twenty-two patients received RT consolidation. RT consolidation was delivered using 3D-CRT, IMRT, or proton therapy. After a median (range) follow-up of 31.8 (2.2-55.1) months, the 3-y event-free survival rate and progression-free survival were 86.9% (69.5-94.7%) and 95% (76.7-99%), respectively. A novel combination of N + BV followed by ISRT was an effective second line therapy. This treatment regimen allowed patients to forgo high dose therapy and transplant in favor of consolidative radiotherapy using ISRT. Larger studies challenging the role of high dose therapy and transplant are needed for RRHL.

TREATMENT STRATEGIES AND PROGNOSTIC FACTORS FOR THE OUTCOME OF PATIENTS WITH HODGKIN LYMPHOMA EXPERIENCING VERY LATE RELAPSES AFTER CHEMOTHERAPY ± RADIOTHERAPY

Background: Despite the excellent long-term outcome of patients with Hodgkin Lymphoma (HL), some cases will be primary refractory or will eventually relapse, mainly within the first 2 years from diagnosis. Patients with sustained complete remission (CR) for ≥5 years are generally considered “cured”. However, Very Late Relapses (VLRs), occurring ≥5 years after treatment initiation, are a non-negligible event and possibly comprise a distinct entity with unique characteristics. Aim: The aim of the current study is to describe the treatment strategies adopted for patients with VLRs as well as their outcome and relevant prognostic factors. Patients/Methods: Patients with HL who experienced VLRs ≥5 years after treatment Initiation with chemotherapy ± radiotherapy (CT±RT), were identified retrospectively from the databases of 8 referral centers. Statistical endpoints were the estimation of time to second failure (TT2F) and Overall Survival after failure (O2S). Results: 145 patients with VLRs were identified. The median age was 49 years (19–82), 69% were males and 18% were ≥65 years old. In 23% of the patients, relapse occurred >15 years after the initial diagnosis. Reinduction with the same regimen was given in 24% of the cases, and 26% were indented to proceeded to high-dose therapy and autologous stem cell transplantation (HDT/ASCT). The 5- and 10-year TT2F were 57% and 53% and the 10-year and 15-year O2S were 59% and 46% respectively. Among 52 deaths, only 28 were disease-related whereas others were attributed to secondary malignancies or unrelated causes. Re-induction with the same regimen did not significantly affect TTF2 and O2S. Despite the numerical difference regarding 5-year FF2P for patients <65 years old who received HDT/ASCT, this was not statistical significant and there was no difference at 10 years. In multivariate analysis B-symptoms, extranodal disease, age ≥65 at relapse, and occurrence of relapse <15 years from diagnosis were independent adverse prognostic factors for TT2F (p = 0.03, 0.003, 0.005 and 0.006 respectively). Anemia, age ≥ 65 and extranodal disease at relapse were also associated with impaired O2S (p = 0.02, <0.001 and 0.044 respectively). We assigned one point to each of the aforementioned unfavorable factors and constructed prognostic scores. Patients combining 2–3 adverse characteristics had significantly compromised outcomes. None of the patients survived at 10-years with the 10-year disease-free-survival being only 36%. Conclusion: The prognosis of VLRs does not appear very favorable, however a considerable proportion of patients were ≥65 years old at the time of relapse when treatment options are limited and also, many patients succumb to disease-unrelated causes. Treatment approaches were heterogenous. In our study B-symptoms, extranodal disease and age ≥65 at relapse were the most important prognostic factors for the outcome of patients with VLRs. Keyword: Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Benefits of Autologous Stem Cell Transplantation for Elderly Myeloma Patients in the Last Quarter of Life

Although survival outcomes have improved dramatically over the last few decades in newly diagnosed myeloma patients, elderly patients have not yielded the same magnitude of benefit as evidenced by higher rates of reported myeloma-related deaths in patients over the age of 75. This is of particular importance given this cohort comprises a large proportion of myeloma patients with the median age of diagnosis being 70 years. One contributor to this discrepancy is reduced use of high-dose therapy and autologous stem cell transplantation (HDT/ASCT) in this population because of concerns for increased toxicity and safety. The objective of this retrospective analysis is to evaluate survival and safety outcomes in 53 newly diagnosed patients ≥74 years of age who underwent HDT/ASCT at our institution in comparison to 122 control patients in the same age bracket who did not undergo stem cell transplantation during this same time period. Patients treated at our institution were identified in our institutional myeloma database by age. They were all treated between November 2006 and October 2016 at the Winship Cancer Institute of Emory University. Fifty-three patients were identified who had undergone HDT/ASCT, and, to assess the relative benefit of ASCT, 122 control patients in the same age range were also identified who did not undergo HDT/ASCT during the same time period. The median age for the entire cohort was 77 years (74 years in the ASCT group versus 78 in the non-ASCT group). Median time to ASCT was 6 months (range 2-57 months). There were no gender or race differences between the 2 groups, although a higher proportion of high-risk patients underwent HDT/ASCT. Ninety-three percent of ASCT patients received triplet induction therapy with a proteasome inhibitor and immunomodulatory agent backbone in comparison to only 55% of patients the non-ASCT group. The median progression-free survival (PFS) for the ASCT group was 50 months versus 30 months in the non-ASCT group. The median overall survival (OS) was 80 months versus 40 months, respectively. In high-risk patients, the median PFS was 60.8 months, and the median OS was 77.8 months in the ASCT group compared to 26 months and 38 months in the non-ASCT group, respectively. There were no transplant-related deaths within the first 100 days in the ASCT group. This study offers real-world perspective and data on the safety and survival benefit of ASCT in the elderly population with a near doubling of OS when compared to those treated with similar regimens and modern agents without ASCT. These data provide a rationale for offering ASCT in elderly patients pending a thorough pretransplantation evaluation.

P13-3 Outcomes and cost effectiveness of treatment of diffuse large B cell non-Hodgkin’s lymphoma with gemcitabine based second salvage chemotherapy

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), it has a 5 year survival rate of around 60-70% and around 50% patients become refractory to treatment or relapse subsequently. Those with relapsed or refractory disease are treated with salvage chemotherapy, using agents different from those used in upfront therapy, followed by high-dose therapy and autologous stem cell transplantation (HDT-ASCT). Around 30-40% of those with relapse or refractory disease who are consolidated with HDT-ASCT after first salvage chemotherapy suffer from relapse. It is a common practice to treat patients with relapsed or refractory DLBCL, with up to 2 lines of salvage chemotherapy. This study analyzes treatment responses and outcomes with respect to progression free survival (PFS) and overall survival (OS) to second salvage chemotherapy in relapsed and/or refractory DLBCL. This was a retrospective analysis of 55 patients of non-Hodgkin lymphoma treated at SKMCH&RC over the span of 25 years, including 55 patients who received gemcitabine based chemotherapy as second salvage regimen. A total of 35 out of 55 patients (63%) patients received GDP 1-6 cycles of GDP with an average number of 3 cycles for each patient. Out of these 35 patients, 22 (63%) were alive at the time of analysis and 8 patients (23%) had died while 5 (14%) had lost to follow up. Our study proves that, in our part of world where rituximab is not available to every patient because of cost limitations, second salvage Gemcitabine based chemotherapy (Gemcitabine/Dexamethasone/Cisplatin) still has a role improving disease free and overall survival.

Using “Big-Data” to Evaluate in-Hospital Morbidity and Mortality in Systemic Light Chain (AL) Amyloidosis after High Dose Therapy and Autologous Stem Cell Transplant (HDT/ASCT)

Background: HDT/ASCT can provide a deep hematological response and result in improvement of amyloid related organ dysfunction in a selected group of AL amyloidosis patients (pts.), but is confounded by substantial treatment-related mortality (TRM) compared to multiple myeloma (MM). However, recent trends have shown improved outcomes of HDT/ASCT in experienced US transplant centers with 30-day mortality of 3%. We performed an analysis of the Nationwide Inpatient Sample (NIS) to compare and better delinate the immediate in-hospital complications and mortality in AL amyloidosis and MM pts. post HDT/ASCT.Methods: The NIS is a large inpatient healthcare database in the US. Unweighted, it contains data from >7 million hospital stays each year and weighted, it estimates >35 million hospitalizations. Full-year data was available for 2008-2013, and this study period was queried to identify patients >18 years of age with a discharge diagnosis of AL amyloidosis and MM after HDT/ASCT conducting a survey weighted domain analysis. Clinical characteristics and in-hospital complications were compared between the two groups using ANOVA test for continuous variables and chi-square tests for categorical variables. Multiple logistic regression was used to compare binary outcomes by AL amyloidosis and MM pts. adjusting for patient characteristics (age, sex, Charlson Co-morbidity Index; CCI).Results: A total of 329 AL amyloidosis pts. were admitted for HDT/ASCT compared to 5302 MM pts. over the 6 year period. The baseline demographics were comparable between the two groups with the exception of CCI (Table 1). Compared to MM, AL amyloidosis pts. were significantly more likely to develop CHF exacerbation (OR 2.69 (95% CI (1.72,4.22); p<0.001); acute renal failure (OR 1.93; 95% CI (1.41,2.66); p<0.001); cardiac arrhythmias (OR 2.19; 95% CI (1.49,3.23); p<0.001); and septic shock (OR 2.14; 95% CI (1.13,4.05); p=0.02); but less likely to develop mucositis (OR 0.56; (95% CI (0.42,0.74); p<0.001) and febrile neutropenia (OR 0.72; (95% CI (0.57,0.91); p=0.005). There was no difference in the use of parenteral nutrition, mechanical ventilation, sepsis and hemodialysis between the groups. Overall, in-hospital mortality in AL amyloidosis pts. was 2.8% compared to 1.3% in MM (p=0.006). On adjusted analysis, there was no difference in in-hospital mortality compared to MM pts. (OR 1.32; 95% CI (0.67, 2.60); p=0.41). The length of stay (LOS) was higher in AL amyloidosis pts. (Mean LOS 20.7 days± 1.01 vs. 17.6 ± 0.52 days; p<0.001) and had higher total hospital charges (mean 185, 000 USD ± 5660 vs. 158,000 ± 8660 p<0.001) compared to MM pts.Conclusions: The results of our large US-population based study showed that AL amyloidosis pts. undergoing HDT/ASCT had increased rates of cardiac and renal complications, higher LOS and total hospital charges immediate post HDT/ASCT compared to MM cohorts. Despite this, there was no difference in adjusted in-hospital mortality between the two groups, underscoring the ever-improving quality of supportive care, better patient selection and effective drugs in treating these pts. This data may help guide informed consent discussions while providing focus for future studies to reduce treatment-related morbidity in AL amyloidosis pts. receiving HDT/ASCT. [Display omitted] DisclosuresDhakal:Celgene: Honoraria. Guru Murthy:Janssen: Other: Fellows advisory board. D'Souza:Prothena: Research Funding; Merck: Research Funding; Celgene: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding.

Assessing Individual Comorbidities in Elderly Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplant — Obesity Associated with Inferior Outcomes

Assessing Individual Comorbidities in Elderly Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplant — Obesity Associated with Inferior Outcomes

High Complete Response Rate Observed with Second-Line Chemo-Immunotherapy with Pembrolizumab and GVD (Gemcitabine, Vinorelbine, and Liposomal Doxorubicin) in Relapsed and Refractory Classical Hodgkin Lymphoma

High Complete Response Rate Observed with Second-Line Chemo-Immunotherapy with Pembrolizumab and GVD (Gemcitabine, Vinorelbine, and Liposomal Doxorubicin) in Relapsed and Refractory Classical Hodgkin Lymphoma

A Phase I/II Dose-Escalation Study of Thiotepa-Based Immunochemotherapy in Relapsed/Refractory Primary Central Nervous System Lymphoma; The Tier Trial

A Phase I/II Dose-Escalation Study of Thiotepa-Based Immunochemotherapy in Relapsed/Refractory Primary Central Nervous System Lymphoma; The Tier Trial

High efficacy and safety of VTD as an induction protocol in patients with newly diagnosed multiple myeloma eligible for high dose therapy and autologous stem cell transplantation: A report of the Polish Myeloma Study Group.

The present retrospective analysis evaluated the efficacy and safety of the VTD (bortezomib, thalidomide, dexamethasone) regimen in 205 newly-diagnosed patients with multiple myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (HDT/ASCT) in routine clinical practice. With a median of 6 cycles (range, 1–8), at least partial response was achieved in 94.6% and at least very good partial response (VGPR) was achieved in 67.8% of patients. Peripheral neuropathy (PN) grade 2–4 was observed in 28.7% of patients. In 72% of patients undergoing stem cell mobilization one apheresis allowed the number of stem cells sufficient for transplantation to be obtained. Following HDT/ASCT the sCR rate increased from 4.9 to 14.4% and CR from 27.8 to 35.6%. The results demonstrated that VTD as an induction regimen was highly efficient in transplant eligible patients with MM with increased at least VGPR rate following prolonged treatment (≥6 cycles). Therapy exhibited no negative impact on stem cell collection, neutrophils and platelets engraftment following ASCT. Therapy was generally well tolerated and PN was the most common reason of dose reduction or treatment discontinuation.

The role of pembrolizumab in relapsed/refractory primary mediastinal large B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBCL comprises approximately 10% of DLBCLs, thus making it a rare variant of DLBCL. Cure rates for PMBCL with upfront regimens like DA-REPOCH exceed 90%. However, if there is a poor response to this first-line therapy, relapsed/refractory PMBCL (rrPMBCL) has limited treatment options. The historic trend is to treat rrPMBCL with salvage regimens commonly used for DLBCL followed by high-dose therapy and autologous stem cell transplant (HDT-ASCT); however, response rates to salvage therapy remain low and few patients are able to proceed to transplant. An interesting feature of PMBCL is that even though it is classified as a subtype of DLBCL, PMBCL actually shares many clinical, pathologic, and genetic features with classical Hodgkin lymphoma (cHL). For example, both frequently express program death ligand 1 and 2 (PD-L1/2), which is not seen in other mature B-cell lymphomas. The expression of PD-L1/2 in PMBCL makes PDL1 inhibitors, such as pembrolizumab, an attractive therapeutic target. Pembrolizumab is an effective and well-tolerated therapy now approved for a number of cancer types from advanced melanoma to relapsed/refractory cHL. There are now multi-institutional trials underway assessing the role of pembrolizumab in the treatment of rrPMBCL.

Where Do the New Drugs Fit in for Relapsed/Refractory Hodgkin Lymphoma?

The standard approach for relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) following frontline treatment failure is salvage therapy followed by consolidation with high-dose therapy and autologous stem cell transplant (HDT/ASCT). While this overall treatment paradigm has been in place for several decades, recent studies have aimed to improve the efficacy and tolerability of salvage therapies by incorporating newer drugs, such as brentuximab vedotin (BV) and checkpoint inhibitors. Following HDT/ASCT, survival is improved due to the availability of BV and the checkpoint inhibitors, nivolumab and pembrolizumab; however, for patients responding to checkpoint inhibition, the appropriate length of treatment and the role of allogeneic stem cell transplant are unclear. In this review, we discuss our management of rel/ref HL, with particular focus on how BV, nivolumab, and pembrolizumab are currently incorporated into the treatment paradigms for rel/ref HL.

160 - Early Toxicities Associated with Radiation Based Conditioning for Relapsed/Refractory Hodgkin Lymphoma Patients Undergoing High Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT)

160 - Early Toxicities Associated with Radiation Based Conditioning for Relapsed/Refractory Hodgkin Lymphoma Patients Undergoing High Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT)

Toxicities and Outcomes for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Pharmacokinetically-Targeted (PK) Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

Toxicities and Outcomes for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Pharmacokinetically-Targeted (PK) Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

▪Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables.Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods.Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction.Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity.Table 1Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic ToxicitiesNumber of Clinically Significant Grade 3-5 ToxicitiesPre-ASCT VariablesAll (N=34)Fewer than 4 (N=21)4 or more (N=13)p-valueAge0.71<6023 (68%)15 (71%)8 (62%)≥6011 (32%)6 (29%)5 (38%)Gender0.72Female13 (38%)9 (43%)4 (31%)Male21 (62%)12 (57%)9 (69%)Disease0.30PCNSL19 (56%)10 (48%)9 (69%)SCNSL15 (44%)11 (52%)4 (31%)KPS0.99≥8032 (94%)20 (95%)12 (92%)<802 (6%)1 (5%)1 (8%)BMT HCT CI0.99≤217 (50%)11 (52%)6 (46%)>217 (50%)10 (48%)7 (54%)Number of Prior Regimens0.04≤221 (62%)16 (76%)5 (38%)>213 (38%)5 (24%)8 (62%)WBRT0.17No28 (82%)19 (90%)9 (69%)Yes6 (18%)2 (10%)4 (31%)Disease state prior0.99CR/CRu29 (85%)18 (86%)11 (85%)PR5 (15%)3 (14%)2 (15%) [Display omitted] [Display omitted] [Display omitted] DisclosuresBhatt:Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Outcomes of Pharmacokinetically (PK) Directed Busulfan in Combination with Thiotepa & Cyclophosphamide (TBC) Conditioning with HDT-ASCT in Patients with Primary & Secondary CNS Lymphoma

Background: High-dose therapy and autologous stem cell transplantation (HDT-ASCT) with thiotepa/busulfan/cyclophosphamide (TBC) conditioning is effective consolidation for patients with newly diagnosed & relapsed/refractory primary (PCNSL) or secondary CNS (SCNSL) lymphoma. A prospective study by Omuro et al (Blood 2015) showed that chemosensitive patients proceeding to HDT-ASCT with TBC conditioning in first remission resulted in encouraging 2-year PFS and OS, but with significant toxicity & transplant related mortality compared to HDT-ASCT for other lymphomas. To our knowledge, there is limited evidence defining the optimal PK directed busulfan (bu) dosing strategy in patients with CNSL undergoing TBC conditioned HDT-ASCT. We report PK targeted bu in TBC and HDT-ASCT in 22 patients with CNSL between 2011 and 2014.Methods: Twenty two patients with CNSL who underwent TBC conditioned ASCT from 2011-2014 with PK targeted busulfan were included. TBC is thiotepa IV 250mg/m2 on days -9,-8, -7; bu 3.2mg/kg IV on days -6, -5,-4; and cyclophosphamide 60mg/kg IV on days -3 & -2 with stem cell infusion on day 0. Adjusted ideal body weight was used in all patients >125% of ideal body weight. PK analysis of bu levels obtained after first dose was by high performance liquid chromatography with mass spectrometry. Predicted area under the curve (AUC) was reported based on 6 point kinetics. Target AUC was 4100-5200 umol*min/L (goal 4700 umol*min/L). Dosage adjustments per PK were made on the 3rd dose of bu. All PK modeling was performed using WinNonLin® 6.0 (Centara, Princeton, NJ).Results: Twenty-two patients with primary CNSL (PCNSL, n = 12, 55%) or secondary CNSL (SCNL, n = 10, 45%) from 2011-2014 received TBC conditioning with PK targeted bu. Thirteen (59%) were men and median age was 56 years (range 25-72). Twelve (55%) & 10(45%) patients received 1-2 & 3-6 lines of prior therapy, respectively for remission induction. All patients were chemosensitive prior to HDT-ASCT with 18(82%) patients in complete remission (CR) & 4(18%) in partial remission (PR). Median pre-transplant HCT-CI was 2.5 (range 0-4) and KPS of ≥80 in 20(91%). Median first dose bu AUC was 5550 umol*min/L (range 3268-7464 umol*min/L with median total bu exposure of 14939 umol*min/L (range 11236-19240 umol*min/L). Five (23%) patients were within therapeutic range, 3(14 %) required a median dose increase of 78%, and 14 (64%) required a median dose reduction of 55% to achieve goal bu exposure. Median time to neutrophil and platelet engraftment was 11 (11-14) & 17.5 (13-52) days respectively. All patients experienced grade 3/4 non-hematologic toxicities [11 (50 %) 0-3 & 11 (50 %) ≥ 4 non-hematologic toxicities, respectively]. The incidence of potential treatment related AST/ALT elevations >3 x ULN & t-bili >1.5 mg/dl was n=5(23 %) & n=7(32 %), respectively. Age and pretransplant HCT-CT >2 were not associated with higher bu AUC or exposure (Table 1). Patients who received ≥ 3 prior regimens had a lower initial bu AUC (p = 0.04), but no difference in total bu exposure (p=0.25). There was no difference in requirement for dose reduction by pre-transplant characteristics (e.g. age, HCT-CI, or prior regimens). Median progression free survival (PFS) by 1 year was 68% (95% CI 39-86) & overall survival (OS) 74% (95% CI 44-90).Conclusion:TBC conditioning is effective consolidation for CNSL. PK directed dosing of bu in our study population resulted in a higher than expected bu AUC. Receipt of > 3 prior regimens was the only pre-transplant patient factor associated with lower initial bu AUC. Although we were not able to correlate any other pre transplant patient factors and bu AUC, the overall incidence of regimen related grade 3-5 non hematologic toxicities remain high. With favorable PFS & OS, future studies targeting lower bu AUC per PK are warranted to reduce toxicity.Table 1Pre-ASCT characteristics with Bu AUC and Total Bu ExposureNMedian Bu AUC umol*min/L (Range)p-valueMedian Total Bu Exposure umol*min/L (Range)p-valueAge0.150.48<60165386 (3268 - 7270)14785 (11236 - 19240)≥ 6065926 (5125 - 7464)15007 (12402 - 17038)HCT CI0.430.390-2115608 (3268 - 7464)15774 (11236 - 19240)>2115182 (3718 - 6882)14904 (12136 - 17038)Prior Regimens0.040.251-2125769 (3718 - 7464)15497 (12136 - 19240)3-6105113.5 (3268 - 6510)14785 (11236 - 15994)*Groups were compared using Wilcoxon rank sum test DisclosuresBhatt:Spectrum: Consultancy. Moskowitz:Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; GSK: Research Funding. Giralt:JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study

Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. Seattle Genetics.

Observational Study Alternating R-CHOP21 and R-Cytarabine (3+3 Cycles) for Patients with Newly Diagnosed Mantle Cell Lymphoma Not Eligible for High-Dose Therapy: A Czech Lymphoma Study Group Trial Preliminary Results

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma characterized by frequent relapses and adverse prognosis. Implementation of high-dose cytarabine (HDAC) and incorporation of anti-CD20 antibody rituximab (R) into induction and maintenance, and consolidation with high-dose therapy and autologous stem cell transplantation (HDT-ASCT) significantly improved pt´s outcome. Therapy of the elderly or comorbid (not eligible for HDT-ASCT) is largely based on R-CHOP or R-bendamustin induction with or without R maintenance. Minimal residual disease (MRD) assessment by quantitative PCR (qPCR) from peripheral blood or bone marrow (BM) has emerged as a powerful molecular marker of outcome. Based on the results of the younger pts some centers adopted the use of HDAC in elderly as well, but no data has been presented yet. Aim: We initiated the observational study as a non-intervention, multi-center trial with the primary objectives to prospectively evaluate efficacy of alternating R-CHOP21 and R-HDAC (1 or 2 g / m2, 2 doses a 24 hours) in newly diagnosed MCL pts not eligible for HDT-ASCT. Methods: Primary endpoints were overall response rate (ORR) by PET-CT, and MRD assessment by qPCR after completion of induction. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The choice between 1 and 2 g / m2 cytarabine was left at investigator´s discretion, as well as the rituximab maintenance. Patients with known cardiac co-morbidity could be treated with R-COEP (etoposid 50 mg / m2, D1-D3) instead of R-CHOP. Exclusion criteria included eligibility to HDT-ASCT, ECOG≥ 4, and CNS involvement. Results: Altogether 61 pts (38 men and 23 women, ratio 1.7:1) were enrolled into the study between 16-JUN-2011 and 18-MAR-2014. Median age was 70 years both for men and women. 91.5%, and 80% pts presented with stage 3/4 disease, and infiltration of BM, resp. According to the MIPI, 55.7%, 39.4%, and 4.9% pts had high, intermediate and low risk disease, resp. B-symptoms were recorded in 33.3% of pts. 76.8% and 24.2% pts were diagnosed from the lymph node, and trephine biopsy, resp. 62.8%, 27.9%, and 9.3% pts presented with classical, pleomorphic and blastoid variant MCL, resp. Ki67/MIB1 ≥ 30% was observed in 38% of pts. Bulky disease &gt;5cm, and &gt;10cm, was noticed in 31% and 13% pts. Spleen involvement was observed in 53% pts. Extra-nodal involvement other than BM was histologically confirmed in 11.5% pts. R-CHOP was used in 88% pts (12% pts received R-COEP), 86% pts received 2g / m2 cytarabine (14% pts 1g / m2). 86.3% pts with response were treated with R maintenace. Only one patient was excluded from the study due to unacceptable toxicity. 57.7% pts developed grade 3/4 hematologic toxicity (neutropenia, anemia or thrombocytopenia). Grade 3/4 non-hematologic toxicity occurred in 27.3% pts. All pts had PET-CT restaging after completion of induction. Overall response rate (CR+PR) reached 91.7%. CR and PR rate by PET was 76.7%, and 15%, resp. SD, and progression on therapy was noticed in 3.3%, and 5.0%, resp. Samples for MRD assessment were collected from 41 out of 54 pts, who completed induction and achieved response (CR or PR). At the time of abstract submission 21, 7, and 7 (out of 36 so far evaluated pts) were MRD negative, MRD positive-not quantifiable, and MRD positive-quantifiable, resp. With the median follow-up 19.1 month, there were 7 progressions and 6 deaths. 2-year PFS and OS probability were 83.9% and 88.1%. Conclusion: Alternation of R-CHOP and R-HDAC in newly diagnosed elderly or co-morbid MCL pts represents a promising, very effective and well-tolerated treatment approach that induces high ORR, and MRD negativity. Grant Support: IGA-MZ NT/13072-4, PRVOUK-27/LF1/1 Disclosures No relevant conflicts of interest to declare.

Chemoresistance can be overcome with high-dose chemotherapy and autologous stem-cell transplantation for relapsed and refractory Hodgkin lymphoma

High-dose therapy and autologous stem-cell transplant (HDT/ASCT) is the preferred treatment of chemosensitive relapsed/refractory Hodgkin lymphoma (HL). The role for HDT/ASCT in chemoresistant HL is less well defined. We evaluated long-term outcomes of relapsed/refractory HL patients whose disease was refractory to secondary chemotherapy preceding HDT/ASCT. All HL patients who underwent HDT/ASCT in British Columbia for primary progression (PP, defined as progression within 3 months of initial therapy completion) or first relapse (REL1) were reviewed. Patients were grouped based on response to secondary chemotherapy as sensitive (S), resistant (R), and untested/unknown (U). A total of 256 patients underwent HDT/ASCT for PP (35%) or REL1 (65%) between 1985 and 2011. At median follow-up of 11.7 years, 58% were alive without HL, 36% relapsed; 6% died of transplant-related mortality, 3% secondary malignancies, and 3% unrelated causes. For PP/S, PP/R, and PP/U groups, 10-year FFS were 47%, 31%, and 38%; 10-year OS were 52%, 29%, and 37%, respectively. For REL1/S, REL1/R, and REL1/U groups, 10-year FFS were 64%, 51%, and 81%; 10-year OS were 71%, 59%, and 79%, respectively. In multivariate analysis, resistance to secondary chemotherapy predicted for post-transplant mortality in the PP (P = 0.04) but not REL1 (P = 0.16) groups. In this large uniformly treated cohort of HL patients with long-term follow-up, chemoresistance preceding HDT/ASCT was identified as a poor prognostic factor; however, this factor can be partially overcome by HDT/ASCT, resulting in cure in 30%-50% of patients. HDT/ASCT should therefore be considered in all transplant eligible patients, regardless of responsiveness to salvage chemotherapy.

Favorable Outcomes in Elderly Patients Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

High-dose therapy and autologous stem cell transplantation (HDT-ASCT) can offer potential long-term remission or cure in patients with non-Hodgkin lymphoma (NHL). Limited experience is available on the safety and efficacy of HDT-ASCT in elderly patients. This is a single-center, retrospective study examining outcomes of HDT-ASCT for 202 NHL patients, ages 60 years and older, between January 2001 and December 2012. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age at HDT-ASCT, hematopoietic cell transplantation comorbidity index (HCT-CI), NHL histology, and remission status at the time of HDT-ASCT. The median age was 65 years (range, 60 to 74) and the majority had either diffuse large B cell lymphoma (n = 73, 37%) or mantle cell lymphoma (n = 69, 34%). One hundred and fifteen patients (57%) had high HCT-CI scores at the time of HDT-ASCT. With a median follow-up of 3.6 years (range, 4 to 11.9 years) for survivors, PFS and OS at 3 years were 60% (95% confidence interval [CI], 53% to 68%) and 73% (95% CI, 67% to 80%), respectively. Transplantation-related mortality (TRM) was 4% both at 100 days and at 1 year after HDT-ASCT. Age and HCT-CI score were not associated with OS or PFS, and high HCT-CI did not correlate with TRM. Seven patients (4%) developed secondary myelodysplastic syndrome or acute myeloid leukemia at a median of 35 months (range, 6 to 48) after HDT-ASCT. In this single-center cohort of elderly patients with NHL undergoing HDT-ASCT, this intervention was proven tolerable and effective, with results similar to those of historic controls in younger patients. Our data suggest that age alone should not preclude HDT-ASCT in elderly patients.

A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies

Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplant (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight patients with advanced lymphoma underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporine-A as GVHD prophylaxis. The cumulative incidence of grade II–IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years was 25% (95% confidence interval [CI]: 13–40%) and 44% (95% CI: 28–59%), respectively. Previous high-dose therapy and autologous stem cell transplant (HDT-ASCT) and elevated lactate dehydrogenase (LDH) at the time of allo-SCT resulted in inferior OS. Within this cohort of patients with high-risk lymphoma, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of progression of disease, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT.