scholarly journals Phase I/II Trial of Lenalidomide and High-Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma: Updated Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2269-2269 ◽  
Author(s):  
Nina Shah ◽  
Peter F Thall ◽  
Denái R. Milton ◽  
Qaiser Bashir ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Logistic Regression ◽  
Stem Cell ◽  
Progressive Disease ◽  
High Dose ◽  
Equity Ownership ◽  
High Dose Melphalan ◽  
Bayesian Logistic Regression ◽  
Dose Levels

Abstract Introduction While high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In light of data suggesting safety and synergy in combining novel therapeutics with traditional cytotoxic chemotherapy, we hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control. Methods We conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Initial results after 12.3 months of follow-up were published in 2015; we now present an update with 39.8 months of follow-up. Results 57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose-limiting toxicities were seen, both at dose level 75 mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 4%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). 63% received maintenance therapy, (54% lenalidomide-based). By day +90, 8 patients (14%) had achieved a complete response (CR), 17 (30%) a very good partial response (VGPR), and 17 (30%) a partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. Best responses were PR: 26%, VGPR: 18%, near CR: 18%, CR: 7%, stringent CR: 23% for a ≥VGPR rate of 66. 23% achieved bone marrow minimal residual disease negativity by flow cytometry. Median time to achieve best response was 92 days (range: 16-732). One patient (2%) had progressive disease and 3 patients (5%) achieved only stable disease. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, (deletion 13q, t(4:14) or del 17p) by conventional cytogenetics or (t(4:14), t(14:16) or del17p by fluorescent in-situ hybridization), bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 39.8 months (range: 0.5- 66.9), median PFS was 17.1 months (95% CI: 10.8 - 23.0, Figure 1) and median OS was 48.0 months (95% CI: 22.6 months, not estimated, Figure 2). There was no significant effect of dose level on PFS or OS. Multivariable Bayesian survival time models found high-risk cytogenetics to be significantly harmful to both OS and PFS. In addition, degree of plasma cell infiltration of bone marrow before auto-HCT was significantly harmful to PFS. Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Longer follow-up demonstrates PFS and OS as comparable to other salvage treatments for MM, suggesting that this regime can be applied as a part of the sequence of therapies for these patients. Figure 1 PFS of 17.1 months (95% CI: 10.8 - 23.0; N=57, Events=48) Figure 1. PFS of 17.1 months (95% CI: 10.8 - 23.0; N=57, Events=48) Figure 2 OS of 48.0 months (95% CI: 22.6 months, not estimated; N=57, Deaths=28) Figure 2. OS of 48.0 months (95% CI: 22.6 months, not estimated; N=57, Deaths=28) Disclosures Orlowski: Takeda Pharmaceuticals: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties.

Phase I/II Trial of Lenalidomide and High Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3981-3981
Author(s):  
Nina Shah ◽  
Peter F. Thall ◽  
Patricia S Fox ◽  
Qaiser Bashir ◽  
Jatin J. Shah ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Stem Cell ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
High Dose ◽  
Advisory Committees ◽  
High Dose Melphalan ◽  
Bayesian Logistic Regression ◽  
Dose Levels

Abstract Introduction While high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In the era of modern therapeutics, it is reasonable to consider that the advantages gained for relapsed patients in the conventional setting may also extend to auto-HCT. We thus hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control. Methods We conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier curves were used to estimate PFS and OS and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Results 57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose limiting toxicities were seen, both at dose level 75mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 3%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). By day +90, 8 patients (14%) had achieved a CR, 25 (44%) a CR or very good partial response (VGPR), and 42 (74%) a CR, VGPR or partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. By day 180, 12 patients (21%) had achieved a CR. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 12.3 months (range 0.5-41), median PFS was 23.7 months and median OS had not yet been reached. The 1-year progression-free rate was 64% (95% CI: 49-75%). Multivariable Bayesian survival time models found both dose level and longer time between diagnosis and transplant to be significantly beneficial to both OS and PFS. In addition, high risk cytogenetics and LDH were significantly harmful to OS, and LDH was moderately harmful for PFS as well (Figures 1 and 2). Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Our previous data has shown a median PFS of 12.3 months in a comparable population. Thus this treatment regimen yields an encouraging PFS, offering relapsed or refractory patients another option for disease control. Figure 1. PFS by lenalidomide dose level (N=57, Events=24) Figure 1. PFS by lenalidomide dose level (N=57, Events=24) Figure 2. OS by lenalidomide dose level (N=57, Deaths=12) Figure 2. OS by lenalidomide dose level (N=57, Deaths=12) Disclosures Shah: Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Off Label Use: This presentation discusses lenalidomide in a transplant preparative chemotherapy combination. . Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Champlin:Celgene: Consultancy, Research Funding.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

Long Term Follow-Up of 4-Hydroperoxycyclophosphamide Purged Autologous Bone Marrow Transplantation in Non-Hodgkin’s Lymphoma Patients with High Risk of Bone Marrow Involvement.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5234-5234
Author(s):  
Elise A. Chong ◽  
Charalambos Andreadis ◽  
Stephen J. Schuster ◽  
Selina M. Luger ◽  
David L. Porter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
B Cell ◽  
Tumor Cells ◽  
Platelet Transfusion ◽  
High Dose ◽  
Free Survival

Abstract Introduction: High-dose chemotherapy and autologous stem cell transplant (ASCT) can result in long term survival for patients with advanced non-Hodgkin’s lymphoma (NHL) but relapse remains a common cause of treatment failure. Bone marrow (BM) involvement is common in NHL and there is controversy over whether or not reinfusion of BM stem cells contaminated by clonogenic tumor cells is a major cause of relapse following ASCT. Bone marrow purging can reduce the number of tumor cells in vitro, but the impact on relapse and disease free survival (DFS) remains unknown. Methods: Between 1990 and 1993, 20 pts with poor prognosis NHL (B-symptoms, high LDH, bulky adenopathy, stage III or IV, or relapsed disease) at high risk for BM involvement underwent 4-hydroperoxycyclophosphamide (4-hc) purged BM transplantation. Thirteen pts had low grade B-cell NHL, 6 had an intermediate grade B-cell NHL with a small B-cell component, and 1 had T-lymphoblastic lymphoma. Seven of 20 pts had received ≥3 prior chemotherapeutic regimens. Three pts underwent transplantation in first complete remission and 17 pts were in chemotherapy-responsive relapse. At diagnosis, 11 of 20 pts had documented BM involvement, and at ASCT, 6 of 20 pts had BM involvement (all < 5% involvement at BM harvest). Eighteen pts (90%) received 4-hc purged autologous BM, and 2 pts (10%) received 4-hc purged autologous BM and peripheral stem cell support. High dose regimens included Cytoxan/TBI (85%), BCV(10%), and Melphalan/TBI (5%). The median age was 45 yrs (range: 20–57 yrs). The median nucleated cell count of 4-hc marrow that was reinfused was 2.4 × 108 /kg (range: 0.87–5.5). The median time to granulocyte recovery was 26 days (range: 14–59). Two pts died at days 31 and 35 without achieving platelet transfusion independence. In the remaining 18 pts, the last platelet transfusion was given at a median of 29 days post-marrow infusion (range 18–149), and the median in-patient hospital days was 27 (range: 16–82 days). Results: There were 2 deaths (fungal infection and CNS relapse) during ASCT. One pt died in CR after developing secondary AML 5.34 yrs after ASCT. Post-ASCT, 18 of 20 pts achieved CR (including 1 pt who had no evidence of disease at autopsy), 1 pt had a PR, and 1 pt died during BMT and was not evaluable for response. Median follow-up for the group was 8.2 yrs (range: 0.1–12.4 yrs). At last follow-up, 9 pts remain in CR (1 died of AML in CR), 5 pts had relapsed and remain alive, and 5 pts died of progressive disease. Median follow-up for survivors was 11.1 yrs (range: 5.2–12.4 yrs). 65% of pts remain alive at last follow-up. The median EFS was 9.4 yrs (range: 0.1–12.4 yrs). Those who achieved a CR post-ASCT had a median DFS of 10.6 yrs (range: 1.1–12.4 yrs). At 8.2 yrs, 4/6 pts with involved BM at the time of harvest had relapsed or died compared to 7/14 pts with negative BM which is not significantly different. Conclusion: ASCT using 4-hc BM purging is feasible and can result in long term relapse free survival, even for pts with subtypes of NHL at high risk for BM involvement. Whether 4-hc BM purging is equivalent or superior to immunologic approaches to stem cell processing remains to be determined.

Outcome of IgD Myeloma After Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4354-4354
Author(s):  
Sofia Qureshi ◽  
Manish Sharma ◽  
Chitra Hosing ◽  
Floralyn L Mendoza ◽  
Jatin Shah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Renal Insufficiency ◽  
Stem Cell Transplantation ◽  
Median Time ◽  
Partial Remission ◽  
Progressive Disease ◽  
High Dose ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 4354 BACKGROUND Multiple Myeloma (MM) is a clonal disorder of plasma cells characterized by monoclonal immunoglobulin (Ig) secretion. Immunoglobulin D (IgD) MM constitutes <2% of all myeloma cases and is characterized by a younger age, male predominance, frequent extra osseous disease, amyloidosis, renal insufficiency and a poor prognosis. We retrospectively analyzed the outcome of patients with IgD myeloma transplanted at our institution. METHODS Between August 1988 and June 2008, 15 patients with IgD MM (13 males, 2 females) received autologous hematopoietic stem cell transplantation (auto HCT) at MD Anderson Cancer Center. Twelve patients received high-dose melphalan (200 mg/m2) as preparative regimen; 3 patients received high-dose melphalan in combination with other agents. RESULTS At diagnosis 7/15 (47%) patients had Durie-Salmon stage III disease, 6/15 (40%) had serum creatinine ≥2 mg/dl and 6/15 (40%) had hypercalcemia. Median age at the time of auto HCT was 53 yrs (range 38–64 yrs) and median interval between diagnosis and auto HCT was 12.6 months (range 3-75 months). Prior to auto HCT 11 patients achieved a partial remission (PR), one had a very good partial remission (VGPR), 2 had minimal response (MR) and one patient had no response to induction. Median follow-up in surviving patients was 25 months. Median time to neutrophil engraftment (ANC > 500/dl) was 10 days (range 9–15 days) and for platelet engraftment (>20,000/dl) was 11 days (range 8–16 days). Non-relapse mortality at 100 days was 0%. Complete responses were seen in 6/15 (40%) patients; 3 converted from PR to CR, 2 from MR to CR and one from VGPR to CR. Only one patient progressed within 3 months of auto HCT. Kaplan-Meiers estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 38% and 64%, respectively. Median time to progression was 18 months. One patient with complex cytogenetics including deletion 13q had disease progression 7 months following an auto HCT. He subsequently received an allogeneic transplant, achieved stable disease status and died 11 months later due to progressive disease. Another patient received a second auto HCT for relapse, but died 3 months later due to progressive disease. CONCLUSIONS Patients with IgD MM, despite a higher incidence of renal insufficiency and hypercalcemia at diagnosis, can safely receive auto HCT, with overall response rates, PFS and OS comparable to other MM subtypes. Disclosures: Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase I/II Trial Combining High-Dose Lenalidomide with Melphalan and Autologous Transplant for Multiple Myeloma: A Report of the Phase I Dose-Finding Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3146-3146
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Rebecca Silbermann ◽  
Robin Obryant ◽  
Lisa l Wood ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Progressive Disease ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Autologous Transplant ◽  
High Dose Melphalan

Abstract Abstract 3146 Background: High dose chemotherapy and stem cell transplantation (HDSCT) has been a standard of care for younger patients with adequate organ function since the early 1980s, due to its superiority over standard chemotherapy in prolonging disease-free and overall survival. Immunomodulatory agents, including thalidomide and lenalidomide, have significant single-agent activity and an additive effect when combined with melphalan. Preclinical data suggest an increased DNA damage and an anti-angiogenic effect with the combination. Additive clinical benefits were also observed when the 2 agents were used in combination in non-transplant settings. The antimyeloma effects of both agents are dose-dependent with myelosuppression being the dose limiting toxicity (DLT). This toxicity can be attenuated with stem cell rescue. Purpose: We conducted a phase I/II trial designed to evaluate the safety and efficacy of combining lenalidomide with high-dose melphalan as conditioning for autologous transplant for myeloma. The phase I portion of the study is complete and the results are reported in this abstract. Experimental Design: The enrolled patients included any patients with myeloma, regardless of the status of the disease, undergoing high dose melphalan for autologous stem cell transplantation. The melphalan dose was fixed (200 mg/m2) while the doses of lenalidomode were escalated from 50, 75, 100, and 150 mg/m2 administered orally days -7 to +2 of the transplantation. Dose escalation was based upon a 3+3 phase I design. DLTs were defined as grade ≥4, both hematologic and non-hematologic, occurring between days -7 to -2 which prevents subjects from undergoing stem cell transplantation, or grade 3 or 4 non-hematologic toxicity occurring after day -2 that does not resolve to a grade 2 or less by day +30 after transplantation, or delayed engraftment. The response was assessed at day +100 post transplantation using the International Myeloma Working Group criteria. Results: 13 patients participated in the phase I portion of the study from September 2010 to May 2012. Patients ages ranged from 42– 72 years (median 63 years). Seven patients were undergoing their first autologous transplant with 2 patients having had 2 lines of previous therapy and 5 having one line of therapy. Six patients were undergoing their second transplantationas salvage for control of progressive disease and all had more than 3 lines of prior therapy. At baseline, 5 patients had progressive disease, 1 had SD, 3 had PR, 3 had VGPR and 1 had CR as responses to their most recent lines of therapy. The median time for ANC and platelet engraftment was 10 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. The most common grade ≥ 3 adverse events were myelosuppression, neutropenic fever and electrolyte abnormalities, all of which are commonly observed with single agent high dose melphalan. Adverse events related to the study drugs were electrolyte abnormalities (hypokalemia, hyperkalemia and hypocalcemia), gastrointestinal side effects and rash, all of which were grade 1 to 2 and manageable without a delay or discontinuation of the study drugs. One patient died from disease progression prior to scheduled disease evaluation. One patient has not yet reached day +100 post transplant. Therefore, responses were evaluable for 11 patients. Three patients achieved stringent CR (27%), 3 CR (27%), 2 VGPR (18%), 3 PR (27%) and one had progressive disease (9%). The overall response rate was 91%, with 72% achieving VGPR or better. All patients had adequate count recovery and were able to initiate lenalidomide maintenance treatment by day +100 to +110 post transplantation. Conclusions: The use of high dose lenalidomide in conjunction with high-dose melphalan is well tolerated, with preliminary data suggesting that the combination is highly efficacious. DLT was not observed; therefore the recommended phase II dose is 150 mg of lenalidomide orally on days -7 to +2 in combination with melphalan 200 mg/m2. The phase II portion of this trial is ongoing in patients undergoing first HDSCT. Complete response at 3 months post transplantation is the primary end point. Disclosures: Off Label Use: Lenalidomide in myeloma transplant. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

scholarly journals Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 339-339 ◽  
Author(s):  
Jeanette K Doorduijn ◽  
Monique C. Minnema ◽  
Marie Jose Kersten ◽  
Pieternella J Lugtenburg ◽  
Martin R. Schipperus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Induction Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

scholarly journals High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1381-1390 ◽  
Author(s):  
A Nademanee ◽  
MR O'Donnell ◽  
DS Snyder ◽  
GM Schmidt ◽  
PM Parker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Peripheral Blood Stem Cell ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Prior Chemotherapy ◽  
Autologous Bone ◽  
Total Body

Eight-five consecutive patients with relapsed or refractory Hodgkin's disease (HD) underwent high-dose chemotherapy or chemo/radiotherapy followed by autologous bone marrow (ABMT) and/or peripheral blood stem cell (PBSC) transplantation. Two preparative regimens were used. Twenty- two patients (26%) without prior radiation received fractionated total body irradiation (FTBI) 1,200 Gy in combination with high-dose etoposide (VP-16) 60 mg/kg and cyclophosphamide (CTX) 100 mg/kg. Sixty- three patients (74%) with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. The median age was 32 years (range, 16 to 56). The median number of prior chemotherapy regimens was three (range, 1 to 7). Forty-three patients (51%) received transplants in first relapse or second complete remission (CR), whereas 33 (39%) received transplants after second or subsequent relapse. All relapsed patients, except one, received conventional salvage chemotherapy and/or radiotherapy in an attempt to reduce tumor bulk before transplant. At the time of analysis in April 1994, fifty-seven patients (67%) are alive, including 44 (52%) in continuous CR, with a median follow-up for the surviving patients of 28 months (range, 7 to 66). Thirty patients (35%) relapsed at a median of 9 months (range, 1 to 43). Eleven patients (13%) died of transplant-related complications including veno- occlusive disease of the liver (VOD) in five, acute and late interstitial pneumonitis in three, graft failure in one, cerebral hemorrhage in one, and therapy-induced myelodysplasia (MDS)/acute leukemia in one patient. At a median follow-up of 25 months (range, 0.6 to 66), the cumulative probability of 2-year overall and disease-free survival (DFS) of all 85 patients is 75% (95% confidence interval [CI] 64% to 84%) and 58% (95% CI 47% to 69%), respectively. Three independent prognostic variables were identified by univariate analysis: number of prior chemotherapy regimens, prior radiotherapy, and extranodal disease at ABMT. Multivariate stepwise Cox regression identified the number of prior chemotherapy regimens as the only significant prognostic factor predicting for both relapse and DFS. There were no significant differences in the outcome of the treatment between the two preparative regimens. Our results confirm that high- dose therapy and ABMT is an effective therapy for patients with relapsed or refractory HD. Earlier transplantation is recommended before the development of drug resistance and end organ damage that results from repeated attempts of salvage therapy.

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