Candidates For High-dose Chemotherapy Research Articles

Clinical and economic implications of using daratumubab with lenalidomide in the 1st and 2nd lines of therapy for multiple myeloma patients

Objective: to assess clinical and economic implications of adding daratumumab (Dara) to the “lenalidomide + dexamethasone” (Rd) treatment program in early lines of therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy (HDCT) with subsequent autologous hematopoietic stem cell transplantation (autoHPSCT).Material and methods. Partitioned survival model was developed to compare overall survival in the treatment programs of MM patients in the 1st to 3rd lines of therapy. The following treatment options were included in the analysis: 1st line – Dara+Rd; 2nd line – “carfilzomib + lenalidomide” (K+Rd) or “ixazomib + lenalidomide” (Ixa+Rd) triplets; 3rd line – pomalidomide (Pom+dex) and Rd+(Dara+Rd)+(Pom+dex) versus Rd+(K/Ixa+Rd)+(Pom+dex/Dara). Probabilities of transition between health states (progression-free, progressed disease, and death) were based on published clinical data. Lifetime direct healthcare costs and incremental cost-effectiveness ratios (ICERs) per 1 life year gained were calculated from a Russian health care perspective. The indicator of the difference in costs between current and expected practice was used in budget impact analysis.Results. Dara+Rd combination increased life expectancy by 1.04 years (+16.05%) and 0.95 years (+14.57%) per patient, and in the target population (n=955) by 995.48 and 903.40 years for (Dara+Rd)+(K+Rd)+(Pom+dex) and (Dara+Rd)+(Ixa+Rd)+(Pom+dex) treatment programs, respectively, compared to Rd use in the 1st line. The ICER per 1 life year gained for Dara+Rd in 1st line therapy was 8.95 mln rubles for (Dara+Rd)+(K+Rd)+(Pom+dex) and 8.41 mln rubles for (Dara+Rd)+(Ixa+Rd)+(Pom+dex). It's lower than the median ICER of 13.64 million per 1 life year gained for antitumor drugs used to treat cancer of lymphatic and hematopoietic tissues (reference ICER). Dara+Rd triplet is used in 2nd line therapy after Rd, the number of life years gained in the target population due to greater efficacy is higher by 291.50 years compared with K+Rd and by 203.93 years compared with Ixa+Rd. The ICER per 1 life year gained for Dara+Rd is also lower than the ICER reference value: 9.25 mln rubles versus 13.64 mln rubles. The budget impact analysis showed that using Dara in early stages of MM therapy does not increase drug provision costs in the target population.Conclusion. The obtained results allowed to conclude that it is economically feasible to add Dara to the 1st and 2nd lines of therapy in lenalidomide treatment programs for MM patients who are not candidates for HDCT with autoHPSCT.

Assessment of Effectiveness and Adverse Effect of New Combination Chemotherapy (irinotecan, cisplatin, and dexamethasone) in Relapse and Refractory Hodgkin Lymphoma.

Background: Chemotherapy with Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen) cannot cure all patients with Hodgkin lymphoma. In this study, we evaluated the efficacy and adverse effect of a new regimen consist Irinotecan, Cisplatin, and Dexamethasone (ICD) in relapsed and refractory Hodgkin lymphoma as the second to fifth line of treatment. Materials and Methods: We performed a retrospective study in 26 relapsed or refractory patients with Hodgkin lymphoma receiving at least the first-line chemotherapy regimen (ABVD) and (ICD) as salvage therapy in Thaleghany Hospital from 2012 to 2018. This regimen consisted of Irinotecan 65mg/m2 D1, D8, Cisplatin 30mg/m2 D1, D8, and dexamethasone 40mg D1, 2, 8, and 9 was administered every 3 weeks for 6 cycles. Treatment was discontinued in cases of disease progression or severe toxicity. Response to treatment was evaluated after two cycles. Patients with complete and partial remission were candidates for high-dose chemotherapy and autologous stem cell transplantation. Twenty-four patients were enrolled in the study. The mean age of 22 patients was 31.5 (19-67) years. Seven patients (29.1%) were in the first recurrence, and 17 (70.8%) were in the second or subsequent recurrence. Results: According to this study, three patients (12.5%) had complete response, 13 (45%) had partial response, four (16.6%) had stable disease, and four (16.6%) had progressive disease. Nine patients (37.5%) received high-dose chemotherapy and autologous stem cell support after ICD regimen. None of the cycles of chemotherapy were delayed due to treatment-related adverse event. Overall survival after six months in all patients was 91%, and mortality rate was 8.3% at the end of the study. Conclusion: The goal of salvage chemotherapy in relapsed or refractory Hodgkin Lymphoma is achieving CR or PR preparation patients for stabilization with BMT. Thus, we recommend ICD as one of the most effective protocols with overall response rate of 66% in this population.

A single-arm, phase II study of durvalumab (D) and tremelimumab (T) for relapsed/refractory germ cell tumors (GCT).

5040 Background: Patients (pts) with GCT and progressive disease (PD) after salvage high-dose chemotherapy (HDCT) have dismal outcomes with median progression free survival (PFS) and overall survival (OS) of 1.0 and 4.7 months (mo), respectively (Feldman et al. Cancer 2012). Immune checkpoint blockade (ICB) has resulted in durable benefit in multiple tumor types. We tested D (anti-PD-L1) + T (anti-CTLA-4) for pts with relapsed/refractory GCTs in a phase II trial (NCT03158064). Methods: Eligible pts were ≥ 18 years old with GCT of any primary site who had PD after first-line chemotherapy and HDCT or were not candidates for HDCT or other curative options. Pts received D (1500 mg) and T (75 mg) every 4 weeks (wks) for 4 cycles followed by D (1500 mg) every 4 wks for up to 1 year (schedule 1). The study was later amended to one cycle of D (1500 mg) and T (300 mg) followed by D (1500 mg) every 4 wks for up to 1 year (schedule 2). The primary endpoint was initially overall response rate (ORR) in a Simon’s two-stage design with null and alternate rates of 5% and 20%, respectively. The study was then amended to use a primary endpoint of 16-wk PFS in a new Simon’s two-stage design with null and alternate rates of 5% and 25%. The regimen would be considered promising if 16-wk PFS was achieved in ≥ 3 of 20 pts. Secondary endpoints included PFS, OS, safety, and association of PD-L1 staining with outcome. Results: Between July 2017 and Jan 2022, 29 pts were treated, the last 7 (24%) on schedule 2. Median age was 37 (range, 21-70). Histology was non-seminoma in 25 pts (86%), and primary sites were testis in 20 (69%), mediastinum in 7 (24%), ovary in 1 (3%), and unknown in 1 (3%). Six (21%) pts had late relapse and 21 (72%) received prior HDCT. Median AFP was 310 ng/mL (range, 1–18,087) and HCG 471 mIU/mL (range, 3.3-62,302). Ten pts were treated with the ORR primary endpoint with no responses in stage 1, but 2 pts had tumor reductions of 20% and 22% with PFS of 9.9 and 10.4 mo, respectively, and 1 patient with elevated AFP but no RECIST measurable disease had a PFS of 5.7 mo. Of 19 pts treated with the 16-wk PFS primary endpoint, one had an ongoing partial response (59% tumor reduction) with 33 months follow-up; all others had PD in <16 wks (17 with PD and 1 with stable disease). Thus, the study did not meet its primary endpoint. Among 29 treated pts, the 16-wk PFS was 13.8% (range, 4.3-28.6), and median PFS and OS were 1.4 (95% CI: 4.1, 7.1) and 7.3 mo (95% CI: 3.2, 10.9), respectively. PD-L1 expression data was available for 20/29 pts - 3/13 (23%) with low/negative and 1/7 (14%) with high expression achieved PFS >16 wks. Six (21%) pts had grade 3-4 treatment-related adverse events, 3 (10%) of whom required high-dose steroids. Conclusions: D+T had limited antitumor activity in pts with relapsed/refractory GCT, failing to meet protocol-defined success. However, some pts did appear to benefit, including one exceptional responder. Additional correlative studies are ongoing. Clinical trial information: NCT03158064 .

Daratumumab Based Response Adapted Therapy for Older Adults with Newly Diagnosed Multiple Myeloma: Interim Analysis of Phase II Study

Introduction The combination of daratumumab (DARA), lenalidomide (Len) and dexamethasone (Dex) is an FDA approved therapy for older adults with newly diagnosed multiple myeloma (NDMM) based on the MAIA study. A less intense bortezomib (Bort) lenalidomide dexamethasone combination (VRD lite) is also used. We thought to investigate a personalized daratumumab based response adapted therapy for older adults with NDMM. Methods Patients were required to have NDMM and were age over 65 and not deemed candidates for high dose chemotherapy and autologous stem cell transplant. Eligible patients received subcutaneous DARA and Dex (20 mg PO weekly) for 2 cycles: in the event of partial response or better, patient continued on DARA Dex per usual dose and schedule, in the event of less than a partial response, frailty adjusted dosing of Len or Bort was added to the usual DARA Dex regimen. The choice of Len or Bort was per the treating physician and informed by Ex Vivo drug sensitivity assay. Modified geriatric assessment (including IMWG frailty score, timed up and go) and bone marrow biopsy (for correlatives) were performed at screening as well as on C2D22. Capitalizing on this unique opportunity to examine the tumor and immune response to DARA Dex, additional correlative studies looking at single cell RNAseq and multi-parameter flow cytometry are included. The primary endpoint was best response per IMWG criteria. Secondary endpoints included PFS, ORR after 2 cycles of DARA Dex. Result: Between November 2019 and July 2022 (the data cutoff date), 25 patients were enrolled. The median age was 79 years (range 71-88) and 13 were males (52%). Frailty score per IMWG were 0 (fit), 1 (unfit), 2+(frail) in 16%, 32%, and 52% of patients respectively. Timed up and go was prolonged (>10s) in 7 (35%) patients. High risk FISH (t(4;14) and del17p) was noted in 3 (12%) with an additional 12 patients (48%) with gain 1q/Amp1q. RISS3 was noted in 16% of patients. After 2 cycles of DARA Dex, 23 patients are evaluable for response (2 patients have not yet completed 2 cycles of therapy); 8 patients (35%) had a partial response or better (no patients had progressive disease, 1 patient discontinued therapy after 1 dose of study therapy and a diagnosis of disseminated tuberculosis). Of the 14 patients (61%) with less than a PR, 9 patients had len added and 5 bort added. The overall best response (PR and better) was 95% for this response adapted strategy including CR/sCR, VGPR, PR in 3 (13%), 14 (61%), 5 (21%) respectively. After a median of 14.7 months of follow up on this response adapted therapy, 5 had progressive disease, the estimated PFS at 1 year was 90% (95%CI 65-97.4). Overall, no unexpected toxicity was noted. The most common grade 3+ AE at least possibly related to therapy included neutropenia, anemia, diarrhea, hyperglycemia, agitation and confusion and hypertension each occurring in 4% of patients. The most common possibly related any grade AE occurring in >25% of patients included hyperglycemia 80%, diarrhea 36%, neutropenia 28%, insomnia 28%, fatigue 28% Conclusions: Preliminary results of this DARA based response adapted therapy are encouraging in this mostly frail patient population with a high response rate and low rate of severe AE. Enrollment in this response adapted therapy for older adults with NDMM continues. With longer follow-up, we will integrate correlative studies evaluating the accuracy of ex vivo predictions in response to DARA and combinations in this unique population of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1710: LISOCABTAGENE MARALEUCEL (LISO-CEL) AS SECOND-LINE TREATMENT FOR R/R LARGE B-CELL LYMPHOMA (LBCL) IN PATIENTS NOT INTENDED FOR HSCT: PATIENT-REPORTED OUTCOMES (PRO) FROM THE PHASE 2 PILOT STUDY

Background: The PILOT study (NCT03483103) evaluated liso-cel, an autologous, CD19-directed, chimeric antigen receptor T cell product, as second-line treatment in patients with relapsed or refractory (R/R) LBCL not intended for hematopoietic stem cell transplantation (HSCT). Aims: To analyze changes in health-related quality of life (QOL) with respect to functioning and symptoms in PILOT. Methods: Adults with R/R LBCL after first-line treatment were eligible. Patients were deemed not candidates for high-dose chemotherapy and HSCT by their physician and met ≥ 1 frailty criteria as follows: age ≥ 70 years, Eastern Cooperative Oncology Group performance status of 2, diffusing capacity for carbon monoxide ≤ 60%, left ventricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30), Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS), and EQ-5D-5L health utility index (HUI) and visual analog scale (VAS) questionnaires at screening (baseline), pretreatment (within 7 days before lymphodepletion), preinfusion on the day of liso-cel infusion (Day 1), posttreatment on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study after lisocel infusion, or after disease progression. The PRO-evaluable set included all liso-cel treated patients with baseline and ≥ 1 postbaseline assessments. Linear mixed-effects models for repeated measures assessed the least squares (LS) mean change from baseline for visits with ≥ 10 patients. Meaningful change from baseline was calculated using responder definitions of 10 points for EORTC QLQ-C30, 3 points for FACT-LymS, 0.08 points for EQ-5D-5L HUI, and 7 points for EQ-VAS. Results: Among the PRO-evaluable set (EORTC QLQ-C30, n = 56; FACT-LymS, n = 49; EQ-5D-5L HUI, n = 55; EQ-VAS, n = 54), completion rates were high (≥ 80%) across most visits for all measures. For the EORTC QLQ-C30, mean baseline fatigue was meaningfully worse than in a general population (difference of > 10 points). Overall LS mean changes through Day 545 showed significant improvements in EORTC QLQ-C30 fatigue, pain, and appetite loss, FACT-LymS, and EQ-VAS (Table). Improvement for FACT-LymS was also clinically meaningful. Fatigue improvement was clinically meaningful with a more sensitive minimal important difference of 4 (Cocks et al, 2012). Significant worsening was not observed for any domain. In patient-level analyses, a majority of patients remained stable or achieved clinically meaningful improvement at Month 6 in EORTC QLQ-C30 global health status/QOL (93% of patients), physical functioning (80%), role functioning (90%), cognitive functioning (83%), fatigue (87%), pain (80%), FACT-LymS (96%), EQ-5D-5L HUI (86%), and EQ-VAS (93%). Further, 70% and 60% of patients achieved meaningful improvements in FACT-LymS and EORTC QLQ-C30 fatigue, respectively. Image:Summary/Conclusion: Liso-cel meaningfully improved fatigue and FACT-LymS scores without negatively impacting other QOL measures. These data support the clinical evidence of liso-cel as a potential new second-line treatment in patients with R/R LBCL not intended for HSCT.

P1204: TREATMENT PATTERNS AND REAL-WORLD OUTCOMES IN PATIENTS (PT) WITH LARGE B-CELL LYMPHOMA (LBCL) WHO RECEIVED SECOND-LINE (2L) THERAPY

Background: Pts with LBCL who fail first-line (1L) treatment may be candidates for high-dose chemotherapy (HDCT)/hematopoietic stem cell transplantation (HSCT) if they respond to salvage chemotherapy. However, pts unable to undergo HDCT/HSCT have limited treatment options and often have poor outcomes. Aims: To characterize the demographics, clinical characteristics, treatment patterns, and outcomes in pts with LBCL receiving 2L therapy with or without HDCT/HSCT in the real-world setting. Methods: A retrospective observational study was performed in adult pts with relapsed or refractory LBCL in the United States using electronic health record data from the Flatiron Health database from 01/01/2011 to 09/30/2021. The index date was defined as the 2L therapy start date. Pts were followed from index date until the end of study or death, whichever occurred first. Eligibility criteria included a diagnosis of LBCL, 1L treatment with an anti-CD20 therapy and anthracycline, 2L therapy with or without HDCT/HSCT, and ≥ 12 mo of follow-up. Pt demographics, clinical characteristics, treatment patterns, and overall survival (OS) were examined. Survival probabilities were estimated by Kaplan-Meier (KM) methods. Risk of death between groups was assessed by Cox proportional hazards regression models. Results: Out of 881 pts who met the eligibility criteria, 142 (16.1%) received HDCT/HSCT and 739 (83.9%) did not. Median follow-up time was 17.3 mo. Of all pts, median (range) age was 67.0 yr (19–85), 58.6% were male, 61.9% had stage III or IV disease, and 84.7% received treatment in a community setting. Of pts with/without HDCT/HSCT, median (range) age was 60.0 yr (19–77)/69.0 yr (23–85), 65.5%/57.2% were male, and 69.8%/60.3% had stage III or IV disease, respectively. Among pts with HDCT/HSCT, the most common 2L treatments were rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE)-based (72.5%) and rituximab plus gemcitabine, dexamethasone, and cisplatin (6.3%); the most common third-line (3L) treatments were bendamustine plus rituximab (BR; 12.2%) and lenalidomide plus rituximab (12.2%). Among pts without HDCT/HSCT, the most common 2L treatments were R-ICE (25.3%) and BR (12.2%); the most common 3L treatments were rituximab plus gemcitabine and oxaliplatin (R-GemOX, 11.9%) and R-ICE (8.2%). Pts who received R-ICE might have been intended to proceed to HDCT/HSCT but did not due to lack of response to R-ICE. The median (95% confidence interval [CI]) KM estimates of OS were 22.1 mo (17.9–29.0), 100.0 mo (71.3–not reached), and 15.4 mo (12.9–19.7) in all pts and pts with or without HDCT/HSCT, respectively (P < 0.0001); OS probabilities at 12/24 mo were 60.2%/48.4%, 85.9%/77.3%, and 55.2%/42.8%. Of the 881 pts, 645 (73.2%) and 236 (26.8%) relapsed in ≤ 12 mo and > 12 mo from 1L, respectively. The median (95% CI) KM estimate of OS was 14.3 mo (12.1–18.7) and 47.8 mo (35.8–not reached) in pts who relapsed in ≤ 12 mo versus > 12 mo from 1L, respectively (P < 0.0001; Figure); OS probabilities at 12/24 mo were 54.0%/42.4% and 77.1%/64.9%. The risk of death was significantly greater among pts who relapsed in ≤ 12 mo versus > 12 mo from 1L therapy (hazard ratio, 1.81; 95% CI, 1.45–2.26; P < 0.0001). Image:Summary/Conclusion: Pts with LBCL who did not receive HDCT/HSCT in 2L (including those who were intended but failed to proceed to HSCT) or relapsed in ≤ 12 mo of 1L therapy initiation have a poor prognosis. Significant unmet need exists in pts who were unable to derive the benefit from HDCT/HSCT.

Lisocabtagene maraleucel (liso-cel) as second-line (2L) treatment (tx) for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Patient-reported outcomes (PRO) from the phase 2 PILOT study.

6567 Background: PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed, CAR T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. We analyzed changes in health-related quality of life (QOL) with respect to functioning and symptoms in PILOT. Methods: Adults with R/R LBCL after first-line tx were eligible. Pts were deemed not candidates for high-dose chemotherapy and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF &lt; 50%, CrCl &lt; 60 mL/min, or ALT/AST &gt; 2 × ULN. Pts completed EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L (health utility index [HUI] and VAS) at screening (baseline [BL]), pre-tx (within 7 days before lymphodepletion), preinfusion on day of liso-cel infusion (Day 1), post-tx on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study, or at PD. The PRO-evaluable set included all pts with BL and ≥ 1 post-BL assessments. Linear mixed-effects models for repeated measures assessed the least squares (LS) mean change from BL for visits with ≥ 10 pts. Meaningful change from BL was calculated using responder definitions (in points): 10 for EORTC QLQ-C30, 3 for FACT-LymS, 0.08 for EQ-5D-5L HUI, and 7 for EQ-VAS. Results: Among the PRO-evaluable set, completion rates were high (≥ 80%) across most visits for all measures. For EORTC QLQ-C30, mean BL fatigue was meaningfully worse than in a general noncancer population (difference of &gt; 10 points). Overall LS mean changes through Day 545 showed significant improvements in EORTC QLQ-C30 fatigue and pain, FACT-LymS, and EQ-VAS (Table). Improvement for lymphoma symptoms was also clinically meaningful. Fatigue improvement was clinically meaningful with a more sensitive minimal important difference of 4 (Cocks et al, 2012). Significant worsening was not observed for any outcome. In individual patient-level analysis, 70% of pts demonstrated meaningful improvement in FACT-LymS at month 6. Conclusions: Liso-cel meaningfully improved fatigue and FACT-LymS scores without negatively impacting other QOL measures. These data support the clinical evidence of liso-cel as a potential new 2L tx in pts with R/R LBCL not intended for HSCT. Clinical trial information: NCT03483103. [Table: see text]

Successful "on-demand" plerixafor for autologous peripheral blood stem-cells transplantation for relapsed/refractory germ cell tumors.

BackgroundGerm cell tumors represent, among solid cancers, a potentially curable disease even if up to 20% to 30% of patients (pts) relapse after first‐line treatment especially considering intermediate and poor prognosis groups. In this scenario, patients are candidates for high‐dose chemotherapy and autologous stem‐cells transplantation as second‐line treatment even though stem‐cells mobilization potential can be affected by several cycles and regimens of chemotherapy. To date, plerixafor is authorized in poor mobilizer adult pts diagnosed with lymphoma or multiple myeloma and in pediatric solid tumors or lymphoma. Therefore, the use of plerixafor in adult pts with relapsing/refractory GCT is still off label.Materials and methodsIn our study, we describe mobilization and collection of peripheral blood stem cells for 10 pts with germ cell tumors. Six patients underwent plerixafor administration since classified as poor mobilizers based on WBC count (>5.000/μL) and CD34+ cell count (<15/μL) the day before apheresis procedure.ResultsOn the first day of apheresis, plerixafor administration in poor mobilizers made possible a remarkable boost of CD34+ cells in such a way to overlap that of good mobilizers' (32/μL vs 35/μL, respectively, P > .05).ConclusionTherefore, in our experience, plerixafor made a good fraction of poor mobilizer patients eligible for mobilization and collection and able to undergo the predicted autologous stem‐cells transplantation; thus, the lack of access to the use of plerixafor in this setting of patients risks jeopardizing an effective treatment, especially in case of poor prognosis.

Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5)

Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5)

Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Systemic Approach to Recurrent Primary CNS Lymphoma: Perspective on Current and Emerging Treatment Strategies.

There is no uniform standard of care for the treatment of refractory or recurrent primary central nervous lymphoma (r/r PCNSL). Many different systemic treatment regimens have been studied, but available data are based on small prospective or retrospective reports. There have been no randomized controlled trials in r/r PCNSL to date. Here, we provide an overview of published systemic regimens for the treatment of r/r PCNSL, as well as therapies that are under investigation. In addition, based on available data, we propose strategies of how to approach choice of therapy for different groups of patients in this disease setting. Patients can be mainly divided into three groups: 1) patients suitable for a re-challenge with high-dose methotrexate (HD-MTX)-based regimens and that may or may not be candidates for consolidation with high-dose chemotherapy with autologous stem cell transplant, 2) patients refractory to HD-MTX or that had early relapse, but suitable for an aggressive treatment strategy with re-induction with non-MTX-based therapy, possibly followed by high-dose chemotherapy with autologous transplant, and 3) patients not suitable for re-treatment with HD-MTX and that are not candidates for aggressive therapy. As PCNSL is a rare disease and as there is urgent need for better outcomes in r/r PCNSL, clinical trial participation is encouraged, especially in elderly or frail patients who are not candidates for high-dose chemotherapy and transplant.

Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Treatment of Relapsed DLBCL

Approximately one third of patients with DLBCL will relapse and require second line therapy. Currently patients are stratified by those who are candidates for high dose chemotherapy with curative intent, or patients who are not candidates for high dose chemotherapy and area managed palliatively. Patients who are sufficiently young and fit for intensive therapy undergo second line treatment with a non-cross-resistant chemotherapy regimen such as R-ICE, R-DHAP, or R-GDP, each of which has similar efficacy in this setting. Patients with chemotherapy-sensitive disease proceed to high dose chemotherapy with autologous stem cell support. Unfortunately, this strategy cures fewer than half of relapsed DLBCL patients in the modern era, including only a very small proportion of patients who relapse less than a year after initial R-CHOP.

B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): An open-label, randomized phase II/III trial.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.

Infusion of Ex Vivo Expanded Allogeneic Cord Blood-Derived Natural Killer Cells in Combination with Autologous Stem Cell Transplantation for Multiple Myeloma: Results of a Phase I Study

Background: Multiple myeloma (MM) is an incurable disease thought to be characterized by immune dysregulation and exhaustion, whereby proliferation of malignant plasma cells is not checked by the native immune system. Long term remissions in some patients after allogeneic stem cell transplant (SCT) suggest a graft versus myeloma effect; however the treatment-related toxicity limits the widespread use of this modality. Allogeneic natural killer (NK) cells are active in various hematologic malignancies and may have a role against MM, without concomitant graft versus host disease (GVHD). Umbilical cord blood is a potential source for allogeneic NK cells and ex vivo expanded umbilical cord blood-derived NK (CB-NK) cells demonstrate activity comparable to that of peripheral blood-derived NK cells. We describe here the results of a phase I, first-in-human study of ex vivo expanded allogeneic CB-NK cells in conjunction with high dose chemotherapy and autologous SCT.Methods: Patients with symptomatic MM who were appropriate candidates for high dose chemotherapy and autologous SCT were eligible. CB units with at least 4/6 match at HLA-A, B and DR were chosen for each patient. When possible, CB units with potential NK alloreactivity were prioritized. On day (-19) CB units were thawed and mononuclear cells (MNCs) were isolated by ficoll density gradient centrifugation. MNCs were cultured in a gas permeable bioreactor with irradiated (100 Gy) K562-based aAPCs expressing membrane bound IL-21 "Clone 9.mbIL21" (2:1 feeder cell:MNC ratio) and IL-2 (100 IU/mL). On day 7, cells were CD3-depleted via immunomagnetic depletion and remaining cells were re-stimulated with aAPC feeder cells and cultured for an additional 7 days. NK cell purity was determined after 14 days of culture. Due to pre-clinical data demonstrating synergy between lenalidomide and NK cells, patients received lenalidomide (10 mg orally daily) from days (-8) to day (-2). Melphalan 200 mg/m2 was given intravenously on day (-7). Freshly expanded CB-NK cells were infused on day (-5). Autologous peripheral blood progenitor cells (PBPC) were infused on day (0).Results: 12 patients have been enrolled thus far with 3 patients each on the following CB-NK cell dose levels: 5 e6 NK cells/kg, 1 e7 NK cells/kg, 5 e7 NK cells/kg and 1 e8 NK cells/kg. 11/12 patients had at least 1 high-risk feature of progressed/relapsed disease (n=7), high-risk cytogenetics (n=2) or International Staging System III disease (n=3). Successful NK expansion to target dose was achieved in all patients with median NK purity (CD56+/CD16+/CD3-) of 98.9% (96.8-99.7). Expanded cells demonstrated cytotoxicity against classic K562 and MM cell line targets. There were no infusional toxicities and no occurrence of GVHD. One patient (1 e8 NK cells/kg) failed to engraft due to a poor PBPC graft quality; this patient was rescued with a back-up autologous PBPC graft. There have been no other significant adverse events and no second primary malignancies. 11/12 patients are evaluable beyond day 100. Best response has been 8/12 nCR or better, 2/12 VGPR and 1/12 PR. 4/12 patients have progressed at a median of 330 days. By DNA microsatellite chimerism analysis, donor CB-NK cells were detected in 2 patients at the 1 e7 NK cells/kg dose and all 3 patients in the 1 e8 NK cells/kg dose, for at least 5 days after infusion. By a more sensitive flow cytometric chimerism assay using HLA class I-specific antibodies for donor or recipient, donor CB-NK cells were detected in 3 evaluable patients at doses of 1 e7 NK cells/kg, 5 e7 NK cells/kg and 1 e8 NK cells/kg for at least 12 days after infusion. Further analysis of these cells indicated persistence of an activated phenotype (NKG2D+/NKp30+) in vivo.Conclusion: CB-NK cells can be activated and expanded to clinical scale. This is the first clinical study of CB-NK cells for MM. When infused in the setting of myeloablative chemotherapy, up to 1 e8 allogeneic CB-NK cells/kg are well tolerated with no infusional toxicities or GVHD. These cells can persist for at least 12 days in vivo and demonstrate an active phenotype. Though clinical data are early, responses are encouraging in this high-risk patient population. Further updated data will be presented at the annual meeting. DisclosuresOff Label Use: Lenalidomide with high dose chemotherapy and autologous stem cell transplantation. Kaur:UT MD Anderson Cancer Center: Employment. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Forma Therapeutics: Consultancy. Cooper:Intrexon: Equity Ownership, Patents & Royalties, Research Funding; ZIOPHARM Oncology: Employment, Equity Ownership, Patents & Royalties, Research Funding. Lee:Cyto-Sen: Equity Ownership; Ziopharm: Equity Ownership; Intrexon: Equity Ownership.

Immunotoxin - a new treatment option in patients with relapsed and refractory Hodgkin lymphoma.

BackgroundEven though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT) and autologous hematopoietic cell rescue (SCT). On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options.ConclusionsA new treatment option in this population is an immunotoxin Brentuximab vedotin composed of a CD30 directed antibody linked to the antitubulin agent monomethyl auristatin E. It has demonstrated a substantial effectiveness and an acceptable toxicity. In the pivotal study, the overall response rate was 75% with 34% of complete remissions. The median durations of response were 20.5 and 6.7 months for those with complete remission and all responding patients, respectively. The median overall survival was 40.5 months (3-years overall survival 54%) and the median progression-free survival 9.3 months. The most common non-hematologic toxicities were peripheral sensory neuropathy, nausea, and fatigue while the most common severe side effects were neutropenia, thrombocytopenia, anemia, and peripheral sensory neuropathy.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients (Pts) with Multiple Myeloma (MM) Who Are Not Candidates for High Dose Chemotherapy

Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in pts who are ineligible for high dose chemotherapy. Outcomes are more attenuated in pts > 75 yrs old. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for pts with MM. Here we present the updated results of this ongoing trial. Methods Pts with newly diagnosed active MM who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Pts had the option to continue treatment up to 8 cycles or 2 cycles beyond confirmed CR. An interim analysis found this combination to be efficacious but relatively toxic. As a result, the treatment schema was amended to the following: bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Pts achieving at least SD continued on to maintenance bortezomib 1.3 mg/m2 IV/SQ every 2 weeks for 2 years. Acyclovir or equivalent viral prophylaxis was originally recommended and became required on the modified schema. Responses were assessed using the IMWG criteria. The overall response rate (ORR) was defined as ≥ PR. Adverse Events (AEs) were assessed using the CTCAE Version 4.0. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results As of 5/31/2013, 43 pts have been enrolled (18 on the original schema, 25 on the modified schema). The median age was 75 (45-89) and 39% of pts were > 75 (48% in the modified schema). Forty two percent of pts were ISS II and 32% were ISS III. Fifteen (35%) pts remain on treatment, all on the modified schema. Treatment-related Grade 3 hematologic AEs were seen in 30% of pts. Only 1 treatment-related Grade 4 hematologic AE of neutropenia was observed. Treatment-related Grade 3 non-hematologic AEs were seen in 21% of pts. The most common non-hematologic Grade 3 AE was neuropathy, seen in 12% of pts (all but 1 on the original schema). There was 1 treatment-related Grade 4 non-hematologic AE of atrial fibrillation and 1 treatment related death (congestive heart failure). Herpes Zoster was seen in 19% of the pts, all from the original treatment schema. A total of 40 pts were evaluable for response. The ORR was 83% (55% ≥VGPR, 28% PR) plus 17% SD and 0 PD. Of the 23 evaluable pts on the modified treatment schema, the ORR was 83% (52% ≥VGPR and 31% PR). For the 15 pts > 75, the ORR was 93% (60% ≥VGPR and 33% PR). At a median FU of 13.1 months, the 1-year PFS is 79% (0.53-0.92) and the 1-year OS is 83% (0.54-0.95). Conclusion The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in this elderly pt population with a large number of pts over the age of 75 years. The modified schema is better tolerated allowing pts to proceed to maintenance treatment which may eventually translate to improved results. Enrollment is ongoing. Disclosures: Off Label Use: Off-label use of Bendamustine in the Treatment of Multiple Myeloma. Chu:Teva: Research Funding; Millennium: Research Funding. Boccia:Teva: Research Funding; Millennium: Research Funding. Flinn:Teva: Research Funding; Millennium: Research Funding.

Overview of Pediatric Extracranial Germ Cell Tumors

Germ cell tumors the designation given to neoplasm arising from the cells of the germline, the cells that are destined to become either the egg or the sperm. These tumors have a number of unique features that includes bimodal and wide age distribution, remarkable phenotypic diversity, and varying biologic behavior. During infancy, sacrococcygeal locations predominate with either teratomas in neonates or endodermal sinus tumors in infants above three months. After puberty, non-germinomatous germ cell tumors predominate with gonadal, mediastinal or intracranial tumor. Specific subtypes of germ cell tumors secrete proteins as tumor markers. Surgical resection of the tumor is necessary to establish the diagnosis and for staging of the extent of tumor spread. Except for teratoma, germ cell tumors are highly sensitive to chemotherapy in particular cisplatin. The most commonly used chemotherapy regimen for malignant germ cell tumors is PEB (cisplatin, etoposide and bleomycin). Prognosis is good even in metastatic diseases. Patients with relapsed or recurrent disease may be candidates for high dose chemotherapy and autologous hematopoietic stem cell transplantation. pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2015.22.1.30 Clin Pediatr Hematol Oncol 2015;22:30∼37

A Multi-Center, Non-Randomized Phase 2 Study of Ofatumumab in Combination with ICE-Chemotherapy (O-ICE) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

BackgroundPatients (pts) with DLBCL who have received rituximab (R) antibody in the first-line setting, have poorer treatment outcomes when they are re-treated with R-chemotherapy in the salvage setting. Resistance to R may have developed. Ofatumumab (O) is a human monoclonal antibody against CD 20 that targets a different epitope than R. We hypothesized that replacing R with O in second line setting may overcome R resistance. The primary end-point of this ongoing phase II study is the objective response rate (ORR) following two cycles of O in combination with ICE (Ifosfamide, Carboplatin and Etoposide) or O-ICE. Secondary end points include the assessments of the safety and tolerability of the combination, progression-free (PFS) and overall survival (OS).MethodsThis was a multi-center, non-randomized phase II open label study. Pts with histologically confirmed DLBCL who failed or were refractory to first line R-based anthracycline therapy were eligible. Pts were accrued according to a 2-stage Simon’s Optimal Design at the National Cancer Centre Singapore and 3 medical centres in South Korea; Samsung Medical Centre, Ajou University Hospital and Soonchunhyang University Hospital. Stage 1 will enrol 24 pts and if 14 or more pts respond, we will proceed to stage 2 where another 37 pts would be recruited. Pts receive 3-weekly ICE (Ifosfamide 5g/m2 on day 2, Carboplatin AUC = 5 on day 2, Etoposide 100 mg/m2 day 1-3) and O (1000 mg), infused on day 1 and 8 of cycle 1, and thereafter only on day 1 of each cycle. A restaging scan is performed after cycle 2. Pts who are candidates for high dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) would receive additional 1 or 2 more cycles of O-ICE before stem cell mobilization. Pts who are not candidates for HDC and ASCR would receive up to 6 cycles of O-ICE.ResultsA total of 24 pts with a median age of 54.5 years (27-75) were enrolled. Among them, 14 (58%) were male and 14 (58%) had stage III/IV disease. A median of 4 (2-6) courses of O-ICE was administered and 11 pts underwent HDC+ASCR. The ORR after 2 cycles was 58.3%; complete response (CR) 29.2% and partial response (PR) 29.2%. On treatment completion, the best ORR became 62.5% (CR = 37.5%, PR = 25%). Grade 1/2 non-hematologic toxicities, independent of relation to study drug, occurring in at least 20% of pts included nausea (50%), pain (50%), fatigue (42%), rash (42%), anorexia (33%), vomiting (33%), diarrhea (25%), edema (29%), fever (21%), pruritus (21%), cough (21%) and paresthesia (21%). Grade 3/4 toxicities included neutropenia (50%), thrombocytopenia (71%) and 4 anemia (54%). Febrile neutropenia occurred in 12.5% and no treatment related deaths were reported. The median follow up time was 8.2months (95% CI 5.3-14.0). The median PFS was 8.2months (95% CI 4.2-17.8) and the median OS was not reached (95% CI 8.6-not reached).ConclusionThe study regimen met the predefined threshold of 14 responding pts in stage 1. The ORR of O-ICE was comparable to that of RICE in the CORAL study and this result is significant considering that all pts in this study had received R prior to study entry. Together with the tolerability data and promising activity, continuation of study enrolment in stage 2 has started. DisclosuresTao:Medscape: Honoraria; Takeda: Honoraria. Quek:Novartis: Consultancy, Honoraria; Bayer: Honoraria. Kim:Novartis: Research Funding; Cellgene: Research Funding; Takeda: Research Funding.

Plerixafor added to G-CSF-supported paclitaxel-ifosfamide-cisplatin salvage chemotherapy enhances mobilization of adequate numbers of hematopoietic stem cells for subsequent autografting in hard-to-mobilize patients with relapsed/refractory germ-cell tumors

An appreciable percentage of patients with relapsed/refractory germ-cell tumors (GCTs), candidates for high-dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (HCT), fail to mobilize adequate hematopoietic stem cells (HSCs) numbers with granulocyte colony-stimulating factor (G-CSF)±salvage chemotherapy. Plerixafor has shown a potential to mobilize adequate CD34+HSCs numbers in this context. Here, we applied plerixafor in combination with G-CSF after salvage chemotherapy in 'poor' mobilizers with relapsed/refractory GCTs for HDC+HCT. Patients with relapsed/refractory GCTs (n=10) received salvage paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy+G-CSF to mobilize adequate HSCs to support HDC, mainly with two courses of high-dose thiotepa-etoposide-carboplatin (TEC). Patients failing to achieve the minimum collection threshold of 2.0×10/kg CD34+ cells, to support at least one cycle of HDC, were administered plerixafor before the anticipated HSC collection during subsequent cycle(s). Overall, seven patients mobilized adequate CD34+ cells (>5.0×10/kg) aiming to support two cycles of HDC. Three patients did not mobilize adequate numbers of CD34+ cells after previous G-CSF plus salvage TIP, and plerixafor was added in subsequent cycle(s). This led to a collection of adequate CD34+ cells, able to support HDC with TEC (1-2 cycles). Hematopoietic engraftment for neutrophils (absolute neutrophil count>500/μl) and platelets (platelet count>20 000/μl) with plerixafor-mobilized HSCs occurred after a median of 9 and 14 days, respectively. Salvage TIP+G-CSF leads to successful HSC mobilization in patients with less heavily pretreated GCTs, whereas the addition of plerixafor to G-CSF+TIP led to mobilization of adequate HSCs that supported autografting after one to two TEC cycles.