Induction Therapy with High-Dose Dex Alone in Newly Diagnosed Myeloma Patients Produces a 57% Partial Response and Is Predictive of Progression Free Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3098-3098
Author(s):  
David A. Irvine ◽  
Michael J. Barnett ◽  
Ryan Brinkman ◽  
Donna L. Forrest ◽  
Donna E. Hogge ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Single Agent ◽  
Progression Free Survival ◽  
M Protein ◽  
High Dose ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Depth Of Response ◽  
Best Response

Abstract Induction chemotherapy followed by autologous stem cell transplant (ASCT) has become standard treatment for symptomatic myeloma patients. Our strategy has been to use the Dex component of the VAD protocol alone for 2–4 cycles as induction. Between January 1998 and May 2005, 406 pts were referred to us for treatment of multiple myeloma. We retrospectively reviewed all pts in order to determine the rate and depth of response to Dex, to determine if response predicted overall survival (OS) or progression free survival (PFS) and assess factors predictive of response. Of 406 pts, 124 were excluded due to prior therapy, no treatment or lack of response data. Analysis was performed on 282 pts all of whom received single agent Dex as primary therapy for newly diagnosed myeloma given at 40mg on days 1–4, 9–12, 17–20 every 28 days for at least two cycles. 40% were female and 60% male and median age was 56. Myeloma subtypes were: IgA 21%; IgG 56%; light chain (LC) 17%, nonsecretory 2% and others 1.4%. Cytogenetic information was available in 51% of pts with 53 confirmed as having a deletion on chromosome 13 (del13q). Response to Dex induction therapy was as follows; nCR [no M protein, IF not performed] 4%, PR1 [>90% reduction in M protein/involved Ig subtype] 10%, PR2 [>50% reduction] 43%, MR [>25% reduction] 20%, no response (NR) [within 25% of base level] 14% and progressive disease (PD) [increase by >25%] 7%. 241 proceeded to transplantation; 212 underwent auto SCT with a melphalan based conditioning regimen after stem cell mobilization with cyclophosphamide and GCSF, 29 had an allo SCT. We evaluated the effect of del13q, International Staging System (ISS), b2Microglobin (b2M), sex, age, Salmon-Durie stage, hypercalcemia, Ig subtype, creatinine and hemoglobin at diagnosis (Hgbdx) on response to Dex, OS and PFS from treatment initiation. Univariate analysis showed that OS was significantly affected by Hgbdx >/≤10g/dl, ISS score and b2M >/≤3.5 while PFS was influenced by b2M <3.5, ISS score, and best response to Dex (p<0.001) with those reaching PR1 achieving a median PFS of 1181d and PR2, MR, NR and PD having median PFS of 1031d, 729d, 825d, 61d respectively. In the group proceeding to HDT similar relationships were noted with PFS post transplant (PFSB) significantly affected by ISS score (median survival for ISS I, II and III 1201d, 848d, 621d respectively) [p=0.047], b2M <3.5 (median survival 1225d vs. 621d) [p=0.013] and best response to Dex. Multivariate analysis confirmed depth of response to Dex as a prognostic factor in PFSB. Analysis of factors which might predict which patients are most likely to respond well to Dex using the chi square contingency table demonstrated that ISS score, B2M>2.5 and Ig subtype significantly influenced response (p<0.05). In conclusion; 43% of pts do not achieve at least a PR with single agent Dex induction, and 7% progress. Despite subsequent treatment with high dose Melphalan and autotransplant in most patients in this study, the depth of response to Dex remains predictive of PFS. While it is unknown whether this reflects disease biology, it seems rational to evaluate new lines of anti-myeloma therapy in an attempt to improve depth and frequency of response and evaluate whether this influences long-term PFS.

scholarly journals Cyclophosphamide–bortezomib– dexamethasone compared with bortezomib–dexamethasone in transplantation-eligible patients with newly diagnosed multiple myeloma

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
A. Figueiredo ◽  
H. Atkins ◽  
R. Mallick ◽  
N. Kekre ◽  
A. Kew ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Tertiary Centre ◽  
Depth Of Response ◽  
Cell Mobilization ◽  
Stimulating Factor ◽  
Good Partial Response

Introduction Cyclophosphamide–bortezomib–dexamethasone (CyBorD) is considered a standard induction regimen for transplant-eligible patients with newly diagnosed multiple myeloma (mm). It has not been prospectively compared with bortezomib–dexamethasone (Bor-Dex). We aimed to compare the efficacy of CyBorD and Bor-Dex induction in transplant-eligible patients. Methods In a retrospective observational study at a single tertiary centre, all patients with transplant-eligible mm who received induction with CyBorD or Bor-Dex between March 2008 and April 2016 were enrolled. Progression-free survival (pfs), response, and stem-cell collection for a first autologous stem-cell transplantation (ahsct) were compared. Results Of 155 patients enrolled, 78 (50.3%) had received CyBorD, and 77 (49.7%), Bor-Dex. The patients in the Bor-Dex cohort were younger than those in the CyBorD cohort (median: 57 years vs. 62 years; p = 0.0002) and more likely to have had treatment held, reduced, or discontinued (26% vs. 14.5%, p = 0.11). The stem-cell mobilization regimen for both cohorts was predominantly cyclophosphamide and granulocyte colony–stimulating factor (gcsf). Plerixafor was used more often for the CyBorD cohort (p = 0.009), and more collection failures occurred in the CyBorD cohort (p = 0.08). In patients receiving Bor-Dex, more cells were collected (9.9×106 cells/kg vs. 7.7×106cells/kg, p = 0.007). At day +100, a very good partial response or better was achieved in 75% of the CyBorD cohort and in 73% of the Bor-Dex cohort (p = 0.77). Median pfs was 3.2 years in the Bor-Dex cohort and 3.7 years in the CyBorD cohort (p = 0.56). Conclusions Overall efficacy was similar in our patients receiving CyBorD and Bor-Dex. After ahsct, no difference in depth of response or pfs was observed. Cyclophosphamide–gcsf seems to increase collection failures and hospitalizations in patients receiving CyBorD. Prospective studies are required to examine that relationship.

Analysis of Outcome after Autologous Stem Transplantation in Patients with Newly Diagnosed Myeloma: Comparison of Different Induction Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3079-3079 ◽  
Author(s):  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Suzanne R. Hayman ◽  
S. Vincent Rajkumar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Induction Therapy ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Free Survival

Abstract Background: Autologous stem cell transplantation (SCT) improves survival in patients (pts) with multiple myeloma (MM). We have previously demonstrated that the degree of response at transplant does not impact on the outcome of transplant. However, newer induction regimens such as thalidomide and dexamethasone (Thal-Dex) result in higher response rates compared to previously used regimens such as single agent dexamethasone or vincristine, doxorubicin, and dexamethasone (VAD). We examined the outcome of SCT following three different induction therapies for newly diagnosed MM, namely VAD, single agent Dex, and Thal-Dex. Patients and Methods: 340 patients with MM who received their SCT within 12 mos of diagnosis (median 5.8, range 3–12) were studied. Patients receiving more than one induction therapy as well as those in whom thalidomide was added to dexamethasone for lack of response were excluded from the analysis. There were 105 pts in the VAD group, 140 in the Dex group and 95 in the Thal-Dex group. Responses were defined using standard criteria. Results: The study cohort consisted of 209 males (59%), with a median age of 57 years (range 30–76) at transplant. Baseline characteristics were similar in the 3 groups, except for lower age in the VAD group (median 55.8) compared to Dex (59.6) and Thal Dex (57.4) and shorter time to transplant in the Dex group (5.4 m) compared to VAD (6.4) and Thal Dex (5.9). Markers of disease activity pre-transplant, including B2M and marrow plasma cell percentage were higher in the Dex group compared to either VAD or Thal Dex. The proportion of patients with any response to induction therapy was lower in the Dex group compared to the other two. All pts in the Dex and the Thal-Dex groups received melphalan only conditioning compared to 70% in the VAD group, the rest receiving Melphalan/TBI. An objective response was achieved after SCT in 96%, 97%, and 98% of pts in the VAD, Dex and Thal-Dex groups respectively (P=0.8). A complete response to SCT was seen in 49% of patients in VAD group, 45% among those in the Dex group and 38% among those in the Thal Dex group (P=0.38). There was no difference in the median progression free survival after transplant (P=0.21) or overall survival from diagnosis (P=.34) between the three groups. The proportion free from progression at 2 years post transplant was 54%, 55% and 46% for Dex, VAD and Thal-Dex respectively. The proportion surviving at 4 years from diagnosis was 64%, 65.4% and 72% respectively for the three groups. Conclusion: We did not observe any difference in the response rates including complete responses to SCT in the three groups with nearly all pts in each group achieving a response. The progression free survival and overall survival appear to be comparable between the three groups. The results from initial therapy cannot be compared between the three regimens since the study population is restricted to patients reaching stem cell transplant. Within the limits of the study, there does not appear to be any long term impact of the initial therapy for the patients going onto an early stem cell transplant. Figure Figure

Clinical and Prognostic Relevance of Magnetic Resonance Imaging of the Spine in Newly Diagnosed Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4885-4885
Author(s):  
Patrizia Tosi ◽  
Alessandro Petrucci ◽  
Lucia Pantani ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Involvement ◽  
Progression Free Survival ◽  
High Dose ◽  
Newly Diagnosed ◽  
Resonance Imaging ◽  
Focal Lesions ◽  
Free Survival ◽  
Focal Pattern

Abstract Abstract 4885 Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for a correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, both pattern of bone marrow involvement (focal, diffuse or normal), and number of focal lesions can be detected, and this could contribute to better define the prognosis and the outcome of newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 152 newly diagnosed MM patients (89M, 63F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=43) or double (n=109). Pattern of marrow involvement was normal in 11% of the cases, diffuse in 20% and focal in 69%, with 34% of the patients showing > 7 focal lesions. Patients with a diffuse pattern or a focal pattern with > 7 lesions showed a significantly higher bone marrow plasma cell infiltration (p=0.04) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern with < 7 lesions. Response rate to the assigned treatment program was similar in the three groups of patients, with > VGPR obtained in 63% of the patients with a diffuse pattern, and in 70% of those with a focal pattern. Median progression-free survival (PFS) was significantly longer in patients with < 7 focal lesions as compared to those with >7 lesions or a diffuse pattern (55 vs 46 months p=0.05). Normalization of MRI was more frequently obtained in patients with < 7 lesions (67% vs 38% in patients with > 7 lesions, p=0.005); patients achieving a normal MRI pattern showed a significantly longer PFS (67 months) as compared to patients failing to achieve a negative MRI at the end of treatment (p=0.0000). According to our data, MRI confirms its prognostic role in newly diagnosed MM receiving high-dose therapy and autologous stem-cell transplantation; a diffuse pattern of bone marrow involvement or a focal pattern with > 7 lesions are predictive of a more aggressive outcome of the disease; furthermore normalization of MRI pattern after therapy is predictive of a longer progression-free survival Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2994-2994
Author(s):  
Joseph M. Connors ◽  
Alina S Gerrie ◽  
Maryse M Power ◽  
Kerry J Savage
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Brentuximab Vedotin ◽  
Primary Objective ◽  
Initial Diagnosis ◽  
Cell Transplant ◽  
Free Survival

Abstract Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV. Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy. Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later. Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. Disclosures Connors: Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

scholarly journals Evidence-Based Minireview: Should all newly diagnosed MM patients receive CD38 antibody–based treatment?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 259-263
Author(s):  
Charlotte L. B. M. Korst ◽  
Niels W. C. J. van de Donk
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Free Survival ◽  
Depth Of Response ◽  
Cytogenetic Aberrations ◽  
Number Of Patients ◽  
Pretreated Patients

Abstract CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody–based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

Reduced Intensity Allogeneic Stem Cell Transplantation for Mantle Cell Lymphoma Is Associated with Substantial Late Transplant Related Mortality and a Poor Outcome in Patients with Chemoresistant Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2260-2260 ◽  
Author(s):  
Stephen P. Robinson ◽  
Norbert Schmitz ◽  
Goli Taghipour ◽  
Anna Sureda
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell ◽  
Reduced Intensity ◽  
Related Mortality

Abstract The prognosis for patients with mantle cell lymphoma (MCL) treated with conventional chemotherapy remains poor. Dose escalation and stem cell transplantation has been increasingly employed in an attempt to improve the outcome in these patients. However, due to the advanced age of many patients with MCL, high dose therapy and allogeneic stem cell transplantation is particularly hazardous. Reduced intensity allogeneic transplantation (RIT) may reduce the toxicity of allogeneic stem cell transplantation, facilitate allogeneic engraftment and graft versus lymphoma reactions. However, the results reported to date with this treatment modality have been based on small numbers of patients and provide conflicting results. We have therefore analysed the outcome of a large cohort of patients with MCL reported to the EBMT registry who have undergone RIT. A total of 144 patients (123 male) with a histological diagnosis of MCL were reported by 81 centres. The median age at transplant was 49 years (range 28–68 years) and the median time from diagnosis to transplant was 25 months (range 0.25–13.2 years). The patients had received a median of 2 (range 1–5) lines of prior chemotherapy and 60 (42%) had undergone a prior high dose procedure. At the time of RIT 100 patients had chemosensitive disease, 22 chemoresistant disease and 22 had untested relapse. Patients underwent conditioning with reduced intensity regimens prior to transplantation with allogeneic peripheral blood stem cells (122), bone marrow (20) or both (1). Fully matched sibling donors were used in 109 cases, matched unrelated donors in 21 and 9 patients received mismatched stem cells. 123 of 126 patients assessable for engraftment demonstrated sustained engraftment. With a median follow up of 9 months 84 patients remain alive and 60 have died (15 from progressive disease and 45 from non-relapse mortality). The transplant related mortality (TRM) was 12% at 100 days but by Kaplan-Mier analysis the TRM was 35% at 1 year and 50% at two years. In univariate analysis there was a non-significant trend to a higher TRM in patients with chemoresistant disease (p=0.067) and those with a prior transplant (p=0.062). Patient age and the number of lines of prior therapy had no impact on TRM. At two years following transplant 57% of patients had evidence of disease relapse or progression which was significantly worse in those with chemoresistant disease prior to transplant (p=0.02). The overall survival (OS) at 1 year and 2 years was 55% and 31% respectively and was worse for patients with chemoresistant disease. The progression free survival (PFS) at 1 and 2 year was 43% and 26% respectively. Only disease status at transplantation predicted for a worse PFS. Acute GVHD (grade II-IV) developed in 52 patients and chronic GVHD in 23 patients. Although the early transplant related toxicity is low there remains a significant TRM following RIT for MCL and consequently a low progression free survival. Patients with chemoresistant disease have a particularly poor outcome.

Dose Dense Dreifach* Melphalan100 for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5465-5465
Author(s):  
David Berz ◽  
Elise M. McCormack ◽  
Eric S. Winer ◽  
Patricia Karwan ◽  
Gerald Colvin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Side Effects ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Stem Cell Support ◽  
Peripheral Stem Cell ◽  
Dose Dense ◽  
To Receive ◽  
Cell Support

Abstract Background: Tandem high dose melphalan therapy with autologous peripheral stem cell support has emerged as standard of care for patients without prohibitive comorbidities. Mucositis and gastrointestinal side effects are the most common extrahematologic side effects. Two previously published studies presented a triple transplant with a conditioning regimen melphalan 100mg/m2 (MEL100) with peripheral stem cell support every two to five months schedule. This dose reduced regimen was implemented to limit those extrahematologic dose limiting side effects in the elderly or high risk population. We are presenting a novel approach that investigates the triple melphalan100/m2 approach on a dose dense, every three weeks schedule in a patient population without significant comorbidities for conventional high dose tandem transplantation. Patients and methods: Thirteen standard or high risk patients with stageIII multiple myeloma were prospectively treated This population contained eight patients with IgG clonality, 3 IgA, 1 nonsecretory and one light chain isotype. The induction regimens of the thirteen patients were heterogenous and included 5 VAD, 3 DCIE, 2 Thal/Dex, 2 CIE and 1 pulse decadron. Patients had stem cells harvested through peripheral blood leukopheresis, and these cells were divided into three equal sets and frozen. The patients were scheduled to receive Melphalan at 100mg/m2 on day -1, 20, and 41 and then the autologous infusions occurred at day 0, 21, and 42. Results: All patients were able to receive all three cycles of the MEL100 regimen. Seven patients (54%) received the treatements on the every three week schedule; three treatments (23%) during the second cycle and six treatments (46%) of the third cycle had to be delayed a median of 6 and 4 days respectively. Three patients were managed completely in the outpatient setting, and the average total hospital stay for the three transplants was 18 days. Median progression free survival was 761 days (range 73 – 1571) and the overall survival of this cohort has yet to be reached. No patient had worse than grade II mucositis, and no serious adverse events were recorded. Conclusions: Our regimen of three consecutive autologous peripheral stem cell transplants with a reduced dose of melphalan at 100mg/m2 given every three weeks is very well tolerated. The progression free survival and overall survival are similar and can be compared favorably with the standard tandem myeloma regimens. Although our data is intriguing, further studies with larger numbers need to be performed to confirm these results.

Efficacy and Safety Of Treatments For Relapsed Or Refractory DLBCL: Results Of a Systematic Literature Review

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5104-5104 ◽  
Author(s):  
Ann Colosia ◽  
Peter C Trask ◽  
Robert Olivares ◽  
Shahnaz Khan ◽  
Adeline Abbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Career Development Award

Abstract Background Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of non-Hodgkin’s lymphoma (NHL) cases in Western countries. Although two-thirds of patients may be cured with combination chemotherapy, in the event of treatment failure and for those who are refractory to treatment, survival is usually measured in months. Several therapeutic modalities have been utilized for patients with relapsed or refractory disease, but among patients who are not eligible for high-dose chemotherapy with stem cell transplant, a comprehensive assessment of efficacy and safety is lacking. This systematic literature review (SLR) was designed to exhaustively collect and review information on the clinical efficacy and safety of the different interventions used in the treatment of refractory or relapsed DLBCL, and if possible to perform a meta-analysis. Methods Electronic databases (PubMed, Cochrane Library, Embase) were searched for relevant studies published from 1997 to August 2, 2012. In addition, conference abstracts, bibliographic reference lists of included articles and recent reviews, and the Clinicaltrials.gov database were searched for phase 2, 3, or 4 studies displaying results, potentially unpublished in peer-reviewed journals. Main efficacy outcomes included objective response rate (ORR), complete response, partial response, duration of response, progression-free survival (PFS), and overall survival (OS). Safety endpoints focused on grade 3/4 toxicities and treatment discontinuation due to toxicity. Studies had to report on relapsed or refractory DLBCL after at least one standard treatment and patients who were not eligible to receive high-dose chemotherapy or stem cell transplant (autologous or allogeneic). Mixed type NHL studies were required to report DLBCL outcomes separately for inclusion. Results A total of 3,308 publications were identified in the first pass of a broad SLR on NHL; of these, 57 provided relevant data for DLBCL representing 54 unique studies. Of the 54 studies, there was 1 phase 3 study, 33 phase 2 studies, and 4 phase 1/2 studies (15 studies did not report the study phase and 1 was an observational study). Six studies were comparative (3 randomized trials; 3 nonrandomized trials) with two treatment arms; 48 studies were single arm. Of the 48 regimens evaluated, few regimens were represented more than once. Overall survival and PFS were often not reported or not reported separately for the patients with DLBCL in studies that enrolled patients with any of the multiple lymphoma histologies. Refractory and relapsed criteria were often not defined, and definitions were heterogeneous when available. The ORR from the few comparative studies ranged from 27% to 100%, with most estimates between 40% and 70%. PFS with low and high doses of obintuzumab was 2 months and 3 months, respectively in one study, and OS was 4 months with MEP and 7 months with C-MEP in another study. There was a common regimen in two of the randomized controlled trials, but the patient populations in these studies differed too greatly to allow a valid meta-analysis to be performed. In the single-arm studies, ORR ranged from 11% to 100%, with the estimates evenly distributed across that range. Progression-free survival was approximately 1 to 10 months. Reported median OS ranged from 1 to 13 months. Main safety concerns included thrombocytopenia, leukopenia, and neutropenia. Conclusions There is a high unmet need for effective therapies for patients with relapsed or refractory DLBCL who are ineligible for stem cell transplant. Although numerous regimens have been evaluated in single-arm trials and a handful in comparative studies, there is no clearly superior regimen for patients with relapsed or refractory DLBCL, especially in third- and later lines of therapy. FA is supported by a Clinical Career Development Award from the Lymphoma Research Foundation Disclosures: Colosia: RTI Health Solutions: Employment. Trask: Sanofi: Employment. Olivares: Sanofi: Employment. Khan: RTI Health Solutions: Employment. Abbe: Sanofi: Employment. Police: RTI Health Solutions: Employment. Njue: RTI Health Solutions: Employment. Wang: RTI Health Solutions: Employment. Sherrill: RTI Health Solutions: Employment. Ruiz-Soto: Sanofi: Employment. Kaye: RTI Health Solutions: Employment. Awan: Lymphoma Research Foundation (Career Development Award): Research Funding.

The Mitochondrial Metabolism Inhibitor Cpi-613 in Combination with High Dose Ara-C (HDAC) and Mitoxantrone Is Highly Active in Poor Risk Relapsed or Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2556-2556
Author(s):  
Timothy Pardee ◽  
Kristin Pladna ◽  
Scott Isom ◽  
Leslie Renee Ellis ◽  
Dmitriy Berenzon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Response Rate ◽  
Residual Disease ◽  
Single Agent ◽  
High Dose ◽  
Cell Transplant ◽  
Historical Cohort ◽  
Poor Risk ◽  
Equity Ownership

Abstract Background: CPI-613 is a first in class agent that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. As a single agent CPI-613 was found to be well tolerated with possible activity in several patients with myeloid malignancies.This trial determined the maximum tolerated dose (MTD), safety, and efficacy of CPI-613 in combination with HDAC and mitoxantrone in patients with relapsed or refractory AML. Methods: CPI-613 was given daily on days 1 through 5 starting at a dose of 500 mg/m2. Beginning on day 3, HDAC at 3,000 mg/m2 (or 1,500 mg/m2 for age ≥60) is administered every 12 hours for 5 total doses and mitoxantrone at 6 mg/m2 is given daily for 3 doses. If residual disease is present on day 14 re-induction with the same or a three day abbreviated course could be given. Patients who achieved a complete remission with or without complete count recovery (CR or CRi) could receive up to a total of two additional consolidation cycles with the goal to get responders to stem cell transplant whenever possible. Results: A total of 67 patients have been enrolled and 65 are evaluable. The median age is 60 (range 21-79). Nineteen patients had refractory disease and 14 received at least 1 previous line of salvage therapy. In patients with relapsed disease the median duration of CR1 was 5 months. Cytogenetics were poor risk in 30 patients, intermediate in 30 and good in 6. One patient had CML in myeloid blast crisis. The overall intention to treat response rate was 48% (26CR+5CRi) with a median survival of 6.4 months. In patients ≥60 years old the CR/CRi rate was 42% (15/36). Surprisingly, the response rate for patients with poor risk cytogenetics was 47% (11CR+3CRi) with a median survival of 5.2 months. In a historical cohort treated with HDAC, mitoxantrone and asparaginase at our institution, only 19% (3/16) of patients with poor risk cytogenetics responded with a median survival of 2.8 months. The MTD of CPI-613 in combination with HDAC and mitoxantrone is 2,500 mg/m2. The dose limiting toxicities were diarrhea and nausea. Nine patients (13%) died on or before day 30. The most common toxicities attributed to CPI-613 were diarrhea and nausea, mainly grade 1 or 2. At the time of this submission thirteen patients have gone on to allogeneic stem cell transplantation. Several patients with circulating blasts had blood samples taken before and after CPI-613 infusion. Three of these patients had increased phosphorylation of PDH consistent with its inhibition. Additionally, two patients demonstrated a robust phosphorylation of adenosine monophosphate-activated protein kinase consistent with depletion of ATP. To explore if loss of p53 function (common in poor risk cytogenetics) affected response we tested CPI-613 alone or with an anthracycline against an AML cell line with and without p53 knockdown. Suppression of p53 function resulted in significant resistance to the anthracycline but no change in response to CPI-613; the combination enhanced cell kill over either agent alone. Conclusions: CPI-613 in combination with HDAC and mitoxantrone is a promising salvage regimen, especially in patients with poor risk cytogenetics. Disclosures Pardee: Novartis: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: CPI-613 is a novel anticancer agent not currently approved by the FDA. Ellis:Alexion: Speakers Bureau. Manuel:Novartis: Speakers Bureau. Hurd:Merck: Equity Ownership; Pfizer: Equity Ownership; Medtronic: Equity Ownership; Procter and Gamble: Equity Ownership; Bristol Myers Squib: Equity Ownership. Powell:Celgene: Speakers Bureau; Cornerstone Pharmaceuticals: Consultancy.

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