Interim analysis of a phase 2 minimal residual disease (MRD)-adaptive trial of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) for newly diagnosed multiple myeloma (MM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8011-8011
Author(s):  
Benjamin Avi Derman ◽  
Jeffrey A. Zonder ◽  
Ankit J. Kansagra ◽  
David L. Grinblatt ◽  
Sunil Narula ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Primary Endpoint ◽  
Adaptive Design ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Study Results ◽  
The Impact

8011 Background: The addition of a monoclonal antibody to triplet induction regimens in patients (pts) with MM with intent for autologous stem cell transplant (ASCT) has resulted in higher overall and deep response rates. In this study we are investigating the impact of the addition of Elo to KRd on complete response (CR) and/or MRD-negative rates in newly diagnosed MM regardless of transplant eligibility. Methods: Pts were enrolled from four MM Research Consortium sites into this phase 2 study. All patients receive 12 cycles of Elo-KRd in 28-day cycles: Elo per standard dosing, K 20/56/70 mg/m2 days 1, 8 and 15, R 25 mg days 1-21, and dexamethasone 40 mg days 1, 8, 15, 22. ASCT eligible candidates can undergo stem cell collection after cycle 4 and then resume treatment; pts who elect to proceed to ASCT are censored for response at that time. Pts MRD(-) (<10-5) by NGS after cycles 8 (C8) and 12 (C12) proceed to Elo-Rd until progression. Patients who convert from MRD(+) to MRD(-) between C8 and C12 receive an additional 6 cycles of Elo-KRd (total 18 cycles) followed by Elo-Rd, and pts MRD(+) after C12 receive an additional 12 cycles of Elo-KRd (total 24) followed by Elo-Rd. The primary endpoint of the study is sCR and/or MRD(-) rate after C8 E-KRd. MRD status was determined by ClonoSEQ next generation sequencing (NGS, <10-5) [Adaptive Biotechnologies]. An improvement in the sCR and/or MRD(-) rate by NGS from a historical 30% to 50% at the end of C8 will be considered promising. Results: 44 pts are enrolled, 39 of whom are evaluable for response (cutoff Jan 10 2021). Median age is 62 years (range 43-81, 23% age >70) and 23 (52%) have high-risk cytogenetic abnormalities (HRCA) including 13 (30%) with >2 high-risk abnormalities (6 pts unknown cytogenetics). 34/39 (87%) have MRD trackable by clonoSEQ. The rate of sCR and/or MRD(-) by NGS at the end of C8 is 19/33 (58%), meeting the statistical threshold for establishing efficacy (2 pts censored for elective ASCT before C8 and 4 pts receiving therapy but have not reached C8). With a median follow-up of 24 months, estimated 2-year progression free survival is 87% (100% for standard risk, 79% for HRCA) and estimated 2-year overall survival is 89% (82% for HRCA). No pt who was MRD(-) by NGS after C8 has progressed, including 6 pts with HRCA. Serious adverse events occurred in 30 pts (68%). 89% experienced treatment emergent AEs, the most common (>10%) of which was pneumonia (14%). One pt had grade 5 myocardial infarction. Conclusions: Elo-KRd demonstrates tolerability consistent with known toxicities of these agents and met the primary endpoint of sCR and/or MRD(-) of >50% after 8 cycles. With longer follow-up, the study results may validate that an MRD-adaptive design for de-escalation of therapy in MM can generate deep responses while reducing treatment exposure. Clinical trial information: NCT02969837.

scholarly journals Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1232-1232
Author(s):  
Nicolas Boissel ◽  
Francoise Huguet ◽  
Carlos Graux ◽  
Yosr Hicheri ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Phase 2 ◽  
Early Results ◽  
Grade 5

Abstract Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was &lt;0.01% in 49/88 (56%) of evaluable patients. A total of 40 patients (42%) received an alloSCT. The median number of blinatumomab cycles received in patients not proceeding to alloSCT was 4 cycles (range, 1-5). Thirty-nine severe adverse events (SAEs) were reported: 1 CRS (grade 2), 8 neurotoxicities (1 grade 2, 3 grade 3, 3 grade 4, 1 grade 5), 19 infections, and 11 others. The only grade 5 SAE occurred after alloSCT (seizures). After blinatumomab, a complete MRD response (with at least 0.01% sensitivity) was achieved in 61/82 (74%) evaluable patients and in evaluable patients with pre-blinatumomab detectable MRD. MRD response to blinatumomab was lower in patients with high pre-blinatumomab MRD level, while not impacted by age, WBC, or oncogenic subgroup. With a median follow-up of 20 months, 18-month DFS and OS was 78.8% (95% CI [66.9-86.8]) and 92.1% (95% CI [83.2-96.4]) respectively (Figure 1). Patients with VHR diseases had a worse DFS (68.8%, 95% CI [51.1-81.2]) as compared to other patients (90.6%, 95% CI [72.1-97.1]); p=0.018). This difference of DFS was abrogated by censoring patients at transplant (VHR 88.1%, 95% CI [65.5-96.3] versus others 90.6%, 95% CI [72.1-97.1%], p=0.10). Other factors significantly associated with better DFS were DUX4/ERGdel subgroup, low pre-blinatumomab MRD, and complete MRD response after blinatumomab. Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

scholarly journals Autologous Followed By Allogeneic Versus Tandem-Autologous Stem Cell Transplant in Newly Diagnosed FISH-del13q Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 43-43 ◽  
Author(s):  
Stefan Knop ◽  
Peter Liebisch ◽  
Holger Hebart ◽  
Ernst Holler ◽  
Monika Engelhardt ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Fluorescence In Situ Hybridisation ◽  
Newly Diagnosed ◽  
Treatment Pathways ◽  
The Impact

Abstract Background In multiple myeloma (MM), the introduction of novel compounds into first-line intensive treatment pathways has clearly improved patients’ prognosis. Very recently however, specific molecular cytogenetic abnormalities, lactate dehydrogenase elevation and International Staging System 3 disease were identified to be associated with dismal prognosis despite upfront autologous (auto) stem cell transplant (SCT). Consolidative allogeneic (allo) following initial auto SCT was shown to extend progression-free survival (PFS) as well as overall survival (OS) in some prospective studies on newly diagnosed MM patients (pts). Relatively little is known on the impact of cytogenetic features other than chromosome 13q deletion (del13q) on the outcomes of pts undergoing upfront auto followed by allo (auto/allo) SCT. Patients and methods When the DSMM V treatment program was designed del13q detected by fluorescence in situ hybridisation (FISH) was accepted as one of the distinct risk factors in MM. We therefore used FISH del13q to define the study’s “high-risk” group and aimed to compare tandem high-dose melphalan 200 mg/m² (Mel) with one cycle of Mel followed by reduced-intensity conditioning (RIC) allo SCT. Allocation to either transplant regimen was by availability of an HLA-matched (at least 9/10 matches) related (MRD) or unrelated donor (MUD). Initially, all pts underwent non-novel compound cytoreduction and chemomobilization of peripheral blood stem cells (PBSC). RIC allo SCT was prepared by fludarabine and melphalan (plus ATG in MUD cases). PFS was the primary endpoint. The study was powered to detect an improvement of 2-year PFS from 20% (tandem Mel) to 40.3% (HR, 1.769). Results 199 out of 225 del13q pts with a median age of 53 (range, 30 – 60) yrs who had been enrolled between 10/2001 and 03/2007, were included in the intent-to treat population. Allo SCT was performed in 126/199 pts (63%), 74 of whom (59%) received MUD allografts. At a median follow-up of 49.2 months (mo), 2-year PFS (calculated from day 1 of second SCT) was 59% with auto/allo SCT versus 47% with tandem Mel. Median PFS with auto/allo SCT was 34.5 mo versus 21.8 mo, respectively (p=.005). Two-year non-relapse mortality (NRM) associated with auto/allo SCT was 11.9%. As of yet, there is no difference in OS between the groups, with the median not yet reached for either transplant modality. PFS/OS in auto/allo SCT were independent of donor source (MRD vs MUD). As definitions of cytogenetic risk have evolved over time, we analyzed further FISH abnormalities in pts’ baseline samples: in addition to uniform del13q, 13.6% of pts displayed del17p. Median PFS for del13q/del17p pts after HD Mel was 6 mo versus not reached with auto/allo SCT, respectively (p=.0002). Median OS in del13q/del17p after HD Mel was 23.4 mo versus not reached, respectively (p=.011). In translocation (4;14)/del13q pts (20.7%), median PFS with tandem Mel was 19.3 mo versus 19.1 with auto/allo SCT, respectively (p=.251). Conclusions This prospective trial shows auto/allo SCT to significantly extend PFS when compared to tandem HD Mel in a large cohort of del13q MM pts. It is the first study to demonstrate allo SCT in MM can be safely performed from matched unrelated donors at a reasonable rate of NRM. Utilizing a comprehensive set of FISH cytogenetics, our data for the first time demonstrate allo SCT to specifically benefit patients with high-risk features (del13q/del17p). Incremental gain of PFS when compared to tandem Mel was more than 20 months. Extended OS data on the whole study will be presented. Disclosures No relevant conflicts of interest to declare.

scholarly journals BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years

Blood ◽  
2017 ◽  
Vol 129 (4) ◽  
pp. 456-459 ◽  
Author(s):  
Maria Gavriatopoulou ◽  
Ramón García-Sanz ◽  
Efstathios Kastritis ◽  
Pierre Morel ◽  
Marie-Christine Kyrtsonis ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Probability ◽  
Final Analysis ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Key Points ◽  
Probability Of Response

Key Points BDR is a chemotherapy-free, non-stem-cell–toxic regimen associated with high response rates and long-term remissions. The long-term safety profile of BDR is favorable, with high probability of response to reintroduction of rituximab-based regimens at relapse.

Survival in Patients with Newly Diagnosed Myeloma Undergoing Therapy with Lenalidomide and Dexamethasone: Impact of High-Risk Cytogenetic Risk Status on Outcome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 95-95 ◽  
Author(s):  
Prashant Kapoor ◽  
Shaji Kumar ◽  
Rafael Fonseca ◽  
Martha Q. Lacy ◽  
Thomas E Witzig ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Plasma Cell ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Impact ◽  
Standard Risk

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 617-617
Author(s):  
Melissa Alsina ◽  
Rachid Baz ◽  
Jose L Ochoa ◽  
Jyotishankar Raychaudhuri ◽  
Kara Kosakowski ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Stem Cell Mobilization ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Cell Mobilization ◽  
Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

A Phase I-II Dose Escalation Trial of Clofarabine Plus Melphalan and Thiotepa Followed by Unmodified Allogeneic Stem Cell Transplant (SCT) for the Treatment of High Risk or Advanced Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2354-2354
Author(s):  
Farid Boulad ◽  
Nancy A Kernan ◽  
Susan E Prockop ◽  
Andromachi Scaradavou ◽  
Trudy N Small ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Unrelated Donors ◽  
Disease Free

Abstract Abstract 2354 High-risk or advanced acute leukemias are associated with poor outcome even with the use of stem cell transplantation (SCT) with or without total body irradiation (TBI). Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed a phase I/II protocol using this agent with melphalan (Mel) and thiotepa (Thio) followed by unmodified SCT for the treatment of patients (pts) with high-risk (HR) leukemias. To date, 28 consecutive pts were treated on, or as per protocol, with 26 pts evaluable for follow-up. There were 15 males and 11 females aged 1–58 years (median 5.3 years). Cytoreduction consisted of CLO at dose level I of 20 mg/m2/day × 5 days (n=23) or at dose level II of 30 mg/m2/day × 5 (n=3), Thio 10 mg/Kg/day × 1 day and Mel 70 mg/m2/day × 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF), or tacrolimus and methotrexate. Twenty pts had acute lymphoblastic leukemia (ALL) in complete remission (CR1; n=5), CR2 (n=5), CR3 (n=9), or relapse (n=1). Five pts had acute myeloid leukemia (AML), in CR1 (n=1), CR2 (n=2), or CR3 (n=2). One pt had myelodysplastic syndrome (MDS) in RAEB. For the pts with ALL in CR1, very HR features included: Infant MLL (N=2), Philadelphia (Ph1) chromosome (N=2) and Induction failure (N=1). For the pts with ALL in CR2, HR features included: Infant MLL (N=1), 2nd SCT (N=1), Ph1 and 2nd SCT (N=2), while 1 pt had prior CNS infarcts precluding the use of TBI. The one pt with AML in CR1 had M7-AML. This was a first SCT for 14 pts, a 2nd SCT for 11 pts and 3rd SCT for 1 pt, with time from previous SCT to the present one being 5–73 months (median 11.3 mo) for those 12 pts. Donors were HLA-matched siblings (n=8), HLA matched unrelated donors (n=8), or HLA mismatched unrelated donors (N=10). Stem cell grafts were bone marrow (n=12), peripheral blood (n=7) or double cord blood (n=7) stem cells. Twenty four of the 26 evaluable pts engrafted, while 2 pts died prior to engraftment. Toxicity of the SCT cytoreduction included elevation of hepatic transaminases in 17 of 26 evaluable pts (AST elevation of 5–19 fold and ALT elevation of 7–16 fold), with a subsequent normalization in all pts. Mucositis was mostly at acceptable grade 1–2 levels. Two pts developed a syndrome of renal and hepatic insufficiency leading to hepatic veno-occlusive disease (VOD) (1 pt at each of the 2 dose levels). Non-relapse mortality included: VOD (N=2), infections (N=3), treatment related sarcoma, a malignancy secondary to the irradiation received with a prior transplant (N=1). With a follow-up of 3–57 mos (median 21 mos), 15 of the 26 pts are alive, disease-free. Five pts relapsed and 4 died subsequently of disease, while 6 pts died of non-relapse morality. Overall (OS) and disease-free survival (DFS) at 2 years were both 58%. DFS was 56% for pts > 18 years and 53% for pts < 18 years (p =0.36); it was 64% for recipients of a first HSCT and 41% (p=0.97) for recipients of a second or third HSCT. Five pts (4 recipients of unrelated donor SCT; 3 from mismatched donors) developed Grade 2–4 acute GvHD. Four of these pts went on to develop chronic GvHD. Immune reconstitution was rapid; for the evaluable pts, it included absolute CD4 counts > 200 cells/L at 1–3 mos for 15 pts and at 4–8 mos for 4 pts. This cytoreductive regimen represents a promising approach for the transplantation of patients with high risk acute leukemias. It was well tolerated for pts requiring a second SCT and is also associated with rapid immune recovery. Ultimately, a large scale study would need to be done to determine if this approach could offer equal or superior results to TBI containing regimens for ALL or AML. Disclosures: No relevant conflicts of interest to declare.

A 4-Drug, Weekly Combination Regimen of Bortezomib, Cyclophosphamide, Liposomal Doxorubicin, and Dexamethasone for Initial Treatment of Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5038-5038
Author(s):  
Pamela S. Becker ◽  
Ted A. Gooley ◽  
Kathy Lilleby ◽  
Damian J. Green ◽  
Nicholas Burwick ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Massive Pulmonary Embolism ◽  
Combination Regimen ◽  
Cell Transplant ◽  
Newly Diagnosed

Abstract Abstract 5038 Background: Combination regimens have been highly effective in multiple myeloma. Based on our results with the combination of bortezomib, cyclophosphamide, dexamethsone (Bensinger et al Br J Haematol 2010), we added liposomal doxorubicin to assess whether we could improve response as well as evaluate a weekly combination regimen at our academic center and network affiliated sites in the community. The trial is registered as NCT00849251. Methods: We initially evaluated the regimen in the relapsed setting for toxicity and found it to be well tolerated in 6 patients, then moved to newly diagnosed patients, with the intent that the regimen would serve as induction chemotherapy in preparation for autologous stem cell transplant for transplant-eligible patients. The dosing was bortezomib 1. 6 mg/m2 IV, cyclophosphamide 300 mg/m2 IV, and dexamethasone 40 mg po, days 1, 8, 15, and a single dose of liposomal doxorubicin 30 mg/m2 on day 8 per 28 day cycle. Patients received a maximum of 4 cycles of therapy and the primary endpoints were safety and response at the end of treatment. Results: A total of 31 out of the planned 45 patients (both newly diagnosed and relapsed) were enrolled, as the trial was ended early due to inability to obtain liposomal doxorubicin (Doxil®) for a period of 6 months. One of the relapsed patients was administratively withdrawn after the cycle 1 day 1 treatment. For the remaining 5 relapsed patients who received 2–4 cycles of treatment, the responses were 1 VGPR that was only immunofixation positive, 1 PR and 3 stable disease (SD). For the 24 patients with newly diagnosed MM who completed 1–4 cycles of treatment, there were 2 complete remissions (CRs), 5 VGPRs (2 of which were only immunofixation positive), 11 PRs, and 6 SD for an overall (CR+VGPR+PR) response rate of 75%. Five patients did not complete 4 cycles of therapy, one due to massive pulmonary embolism, one because of need for radiation for intractable back pain during cycle 2 despite marked serological response, and 3 due to stable disease with plateau in response. Of the 25 patients who received BCDD as initial therapy, there have been 3 deaths to date, one due to massive pulmonary embolism on day 13 of the first cycle of treatment, without known history of hypercoagulable risk, one at 7. 7 months of unknown cause, and one at 15. 3 months of progressive disease, resulting in an estimated overall survival of 86% at 2 years from start of therapy. Median follow-up among the 22 survivors is 16. 6 months (range, 8. 1 to 26. 8 months). One patient with a known central line associated deep venous thrombosis in the relapsed group did not exhibit progression of thrombosis off warfarin during therapy. After enrollment of the first 9 patients, an amendment was filed for subsequent patients to receive aspirin prophylaxis, or if at high risk by criteria suggested by Palumbo et al for prophylaxis for MM patients on imids, with low molecular weight heparin or warfarin. Other adverse events that were attributed to investigational regimen include grade 3 hand/foot syndrome (2), infection without neutropenia (1), urinary tract infection (1), and gastrointestinal hemorrhage due to Mallory-Weiss tear (1). Twenty-one patients who completed therapy went on to successful mobilization and collection of peripheral blood stem cells, and autologous or tandem autologous (2) or tandem autologous-minimal myeloablative allogeneic stem cell transplant (7). Two of the 21 patients have died (one at 2. 1 months after first autologous transplant from unknown cause, and one at 9. 8 months from progressive disease). Median follow-up after first autologous transplant among the 19 survivors is 13. 4 months (range, 1. 1 to 20. 4 months). Summary: The 4 drug BCDD regimen exhibited a 75% overall response rate after 4 cycles, with no progression during treatment, was able to be administered weekly in an outpatient setting of both academic and community hematologists and oncologists, and successfully prepared patients for autologous stem cell transplant. Disclosures: Becker: Millennium: Research Funding. Bensinger:Millennium: Research Funding.

HCT.CI in Autologous Stem Cell Transplantation. Predicting Early and Late Transplant Related Mortality

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3449-3449 ◽  
Author(s):  
Mariano Berro ◽  
Maria M Rivas ◽  
Jorge Alberto Arbelbide ◽  
Ana Lisa Basquiera ◽  
Adriana Vitriu ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Hodgkin Lymphoma ◽  
Early Mortality ◽  
Cell Transplant ◽  
End Point ◽  
The Impact ◽  
Autologous Hsct ◽  
Related Mortality

Abstract Background. Hematopoietic Stem Cell Transplant Comorbidity Index (HCT.CI) score, described by Sorror, is a useful tool to assess the risk for Non Relapse Mortality (NRM) after Allogeneic HSCT. The impact of this score in Autologous HSCT is still to be confirmed. Aims. To determine the impact of HCT.Ci score in the morbidity and mortality after autologous HSCT, assessing the 100 day morbidity defined as orothraqueal intubation (OTI), dialysis or shock (defined as vasopressors need), 100 day mortality, early morbi-mortality (combined end-point by any of the previous end-point) and long term NRM. Materials and Methods. We retrospectively reviewed 1478 medical records of adult patients who received an autologous HSCT in our centre between October 2002 and April 2016. Median age was 49 years (range 16-74 years), 58% were male, prevalent diseases were Multiple Myeloma (48%), Non Hodgkin Lymphoma (27%) and Hodgkin Lymphoma (18%), 49% were in complete remission, 46% received one chemotherapy scheme before transplant, 41% two schemes and 12% three or more (heavily pre-treated). In respect to conditionings, melphalan was used in 48% of the cases, CBV in 25%, BEAM in 8% as well as BendaEAM. Seventy five percent received an infusion of stem cells CD34+≥3x10.6/kg. Regarding comorbidities, 58% had low risk (LR) HCT.CI (score 0), 32% intermediate risk (IR) (1-2) and 11% high risk (HR) (≥3). For univariate analysis we use Chi2 for dichotomic variables, Kaplan-Meier for Overall Survival (OS) and cumulative incidence for NRM; for multivariate analysis we used logistic regression for dichotomic and Cox regression for time dependant variables. Results. Median follow up was 1.9 years. Early mortality (day 100) was 2.8%, 5.6% required OTI, 4.8% required vassopresors and 2.2% dialysis, 1-3 years NRM and OS were 4.3-5.2% and 89-77% respectively. High risk HCT.Ci patients had a significant increase in 100 day mortality compared to IR and LR (7% vs.3% vs. 2% respectively, p=0.002), OTI (12% vs. 7% vs. 4%, p<0.001), dialysis (4.5% vs.2.6% vs. 1.5%, p=0.04), shock (10% vs.6.4% vs. 3%, p<0.001), early morbi-mortality (15% vs.9 % vs. 4.6%, p<0.001) and NRM (1-3 years 9.2-13% vs. 3.8-3.8% vs. 3.5-4.5%, p<0.001) (figure 1). After multivariate analysis these outcomes remain significant (showed as OR with 95% CI, IR and HR compared to LR): early mortality (1.8, 0.8-4.2 and 3.9, 1.6-9.7, p=0.003), OTI (2.1, 1.2-3.7, p<0.01 and 3.9, 2.0-7.5, p<0.001), dialysis (2.2, 0.8-5.5 and 4.1, 1.4-11.7, p<0.01), shock (2.7, 1.4-4.9, p=0.001 and 4.4, 2.1-8.9, p<0.001), early morbi-mortality (2.4, 1.4-4.0, p=0.001 and 4.2, 2.3-7.6, p<0.001) and NRM (1.3, 0.7-2.4 and 3.0, 1.5-5.7, p=0.001) (table 1). No significant impact was observed in OS. Other than comorbidities, significant impact was observed in early mortality (pre-transplant status, heavily pre-treated patients and BendaEAM conditioning), OTI (NHL, heavily pre-treated patients, BendaEAM conditioning), dialysis (pre-transplant status and BendaEAM conditioning), shock (NHL, heavily pre-treated patients and BendaEAM conditioning), morbi-mortality (NHL and BendaEAM conditioning) and NRM (male patients, NHL, pre-transplant status, heavily pre-treated patients and BendaEAM conditioning). Conclusions. We observed that HCT.CI had a significant impact on Autologous HSCT treatment related mortality basically due to early toxicity express as 100 day mortality and the three main morbidity outcomes as well as the combined end point. This observation should be confirmed in larger series. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) followed by consolidation high-dose chemotherapy (HDC) and autologous stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma (PCNSL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Antonio Marcilio Padula Omuro ◽  
Denise Correa ◽  
Craig Moskowitz ◽  
Matthew J. Matasar ◽  
Lisa Marie DeAngelis ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Primary Endpoint ◽  
Primary Cns Lymphoma ◽  
Unknown Etiology ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Induction Regimen

2008 Background: In our previous study in newly diagnosed PCNSL, induction chemotherapy with MTX and cytarabine followed by consolidation HDC (carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without radiotherapy resulted in only 50% of pts transplanted, reflecting low efficacy of induction chemotherapy, and short intent-to-treat (ITT) median PFS (=6m). In this phase II trial, we sought to optimize this strategy by utilizing a more effective induction regimen (R-MPV) and a more aggressive HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV (MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC with thiothepa, cyclophosphamide and busulfan was given, followed by ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free survival (promising: 75%, non-promising: 50%; 90% power, significance=0.05). Follow-up included comprehensive neuropsychological evaluation. Results: Accrual has been completed (N=32 pts, median age 57 [range 23-67], median KPS=80). Following R-MPV, 17 pts achieved a CR, 13 pts a PR and two pts progressed. A total of 25 (78%) pts were transplanted; the reasons for not receiving transplant were progressive disease (N=2), poor performance status/ physician’s decision (N= 2), mobilization failure (N=1) and consent withdrawn (N= 2). One pt who withdrew consent relapsed and received HDCASCT for salvage. Two (8%) pts died from early complications of ASCT (Stevens-Johnson: one, sepsis: one) and one pt experienced a fatal late colitis of unknown etiology. In the ITT population, the median EFS and OS have not been reached after a median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90) and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved response rates, allowing 78% of pts to receive HDC-ASCT. Although more toxic, this regimen resulted in excellent disease control and survival in the ITT population, far exceeding the efficacy of our previous transplant study. The primary endpoint was met, warranting further investigation.

Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8589-8589 ◽  
Author(s):  
Noopur S. Raje ◽  
Wolfgang Willenbacher ◽  
Vania Hungria ◽  
Andrew Spencer ◽  
Yulia Alexeeva ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Solid Tumors ◽  
Primary Endpoint ◽  
Stem Cell Transplant ◽  
Phase Iii ◽  
Cell Transplant ◽  
Phase 3

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl < 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

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