High Response Rate to DLI Based Strategies for the Treatment of Refractory Disease/Relapse Following Allogeneic HSCT for Lymphoproliferative Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1653-1653
Author(s):  
Nigel H. Russell ◽  
Jenny L. Byrne ◽  
Emma P. Das-Gupta ◽  
Michelle Gilyead ◽  
Andy P. Haynes
Keyword(s):  
Mantle Cell Lymphoma ◽  
Acute Gvhd ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disease ◽  
High Response Rate ◽  
Low Grade ◽  
High Grade ◽  
Allogeneic Hsct ◽  
Mantle Cell

Abstract Allogeneic HSCT is increasingly being performed for lymphoproliferative disease, particularly with reduced intensity conditioning (RIC). DLI are an important part of this strategy however there is a paucity of information in this setting although responses have been reported in Hodgkin’s disease and follicular lymphoma. We have treated 17 patients (median age 51 year; 30–62yr) with refractory disease (n=7) or disease relapse (n=10) following allogeneic HSCT for lymphoma with a DLI based strategy. The diagnosis was CLL, including 1 Richter’s (n=5); mantle cell lymphoma (n=4); high grade NHL (n=4) and follicular NHL (n=4). 15 patients received RIC transplants with either Beam/Alemtuzumab (n=11), or fludarabine/melphelan/alemtuzumab (n=4). Two patients received myeloablative conditioning with TBI and cyclophosphamide. The median time to DLI was 0.96 years (0.23 to 4.58yr) and in 15/17 the donor was a matched sibling (n=13) or 1 antigen mismatched sibling (n=2) and in 2 cases was an unrelated donor. At DLI, 6 patients had mixed chimaerism (20–95%) and 8 had full donor chimaerism with the chimaerism status being unknown in 5 cases. Patients with low grade disease received DLI either alone (n=7) or following initial radiotherapy (n=1). Patients with high-grade NHL, MCL or Richter’s transformation of CLL (n=11) all received chemtherapy pre-DLI. For the 15 sibling donors the median first dose of CD3+ cells infused was 2.0 x 10 7/kg ( range 0.5–6 x 10 7/kg) following which 6 achieved CR. 6 patients received a 2nd infusion (median dose 5 x 10 7/kg) with 2 achieving CR and 1 patient receiving a 3rd DLI and achieving CR. Both MUD DLI recipients achieved a CR after 2 and 3 infusions. Overall 10 out of 17 patients achieved a CR including 3/4 patients with CLL, 4/4 with MCL; 3/4 with follicular NHL but none of the 5 patients with high-grade NHL/Richter’s transformation responded. The median CD3 cell dose required to achieve CR for sibling donors was 2x 107/kg whereas non-responders received a median of 5.0 x 107/kg. An additional patient with CLL who developed aplasia following the first DLI had a second transplant from the same donor and is in CR at 14m giving a final overall CR rate of 70%. Response to DLI was independent of chimaerism status at relapse. Acute GvHD developed in 11 patients and was grade II in 8/10 and grade 111/IV in 3 cases. 1 patient died in CR of acute GvHD. Chronic GvHD developed in 9 of 11 surviving patients. Only 1 patient with mantle cell lymphoma has relapsed at 18m post-DLI. The median follow-up for the surviving patients is 34m (range 6m–60m). The overall survival at a median of 30 months post DLI is 58%. We conclude that lymphoma patients, particularly those with low grade NHL including mantle cell lymphoma relapsing following an allogeneic transplant have a high response rate to DLI based strategies,superior to that seen in myeloma and comparable to that seen in CML. Furthermore these responses appear durable with a low risk of relapse. Patients with high-grade disease appear to have a poor response rate despite using pre-DLI chemotherapy

Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 619-626 ◽  
Author(s):  
Roberto Chiarle ◽  
Leo M. Budel ◽  
Jeffrey Skolnik ◽  
Glauco Frizzera ◽  
Marco Chilosi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Protein Degradation ◽  
Mantle Cell Lymphoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

High Response Rate After 4 Courses of R-DHAP In Untreated Mantle Cell Lymphoma (MCL) Patients In the Ongoing Phase III Randomized GOELAMS and GELA LyMa Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1758-1758 ◽  
Author(s):  
Steven Le Gouill ◽  
Catherine Thieblemont ◽  
Emmanuel Gyan ◽  
Olivier Tournilhac ◽  
Guy Laurent ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Response Rate ◽  
Phase Iii ◽  
High Dose ◽  
Open Label ◽  
Disease Evolution ◽  
Mantle Cell ◽  
Platinum Salt

Abstract Abstract 1758 Background: The LyMa trial is established as a randomized, open-label, phase III study, to evaluate the efficacy of rituximab maintenance after autologous stem-cell transplantation (ASCT) in untreated mantle cell lymphoma (MCL) patients aged between 18 and 65 years old. The LyMa trial opened in September 2008. As of July 2010, 114 patients have been included. As in many other lymphoma entities, R-CHOP is still considered a standard of care for upfront MCL patients before ASCT. However, only 30–40% of MCL patients reach CR/CRu after R-CHOP. Since the response status (CR vs PR) before ASCT is associated with a better outcome it is important to find new alternative induction chemotherapy regimen. Growing evidences suggest that high-dose aracytine (HA) could be a major drug in MCL and should not be considered only at relapse. Several groups have highlighted a good response rate after upfront HA. More than 80% of the patients reach CR/CRu after intensive hyperCVAD/MTX regimen. The MCL2 trial from the Nordic group and the GELA trials have also demonstrated that higher response rates are achievable by alternating HA and R-CHOP. Therefore, the LyMa trial was designed to use 4 courses of R-DHAP (Rituximab 375mg/m2 D1; Dexamethasone 40mg D1-4; High-dose Aracytine 2×2 g/m2 D2 and Cisplatin 100 mg/m2 D1 but the choice of platinum salt was left at the discretion of local investigator) as induction therapy followed by ASCT using R-BEAM for newly diagnosed MCL patients. According to the design of the trial, only R-DHAP refractory patients (defined as a tumor burden reduction lower than 75% or progression) are eligible for R-CHOP prior ASCT. Aims: The present analysis was performed in july 2010 and aims to evaluate prospectively the response rate after 4 courses of R-DHAP. All patients included before January 2010 (n=64) were eligible for the purpose of this analysis. Patients' characteristics: Median age is 57 years old (range, 30–65) and 53 (83%) patients are males. At time of diagnosis, 49 patients presented with Ann Arbor stage IV disease. All biopsies were centrally reviewed by pathologist experts from the GOELAMS and GELA groups. MCL diagnosis was confirmed in all reviewed cases. Eleven patients had a blastoid variant. Treatment: One patient withdraws is informed consent prior the start of the first cycle of R-DHAP. This patient has been excluded from the present analysis. All the other patients (n=63) have received at least one course of R-DHAP. Over the four courses of R-DHAP, 15, 24, 29 and 33 patients received another platinum salt than cisplatin. Four courses of R-DHAP were administered to 58 patients. For the remaining 5 patients, treatment was stopped for toxicity reason (n=3) or disease evolution (n=2). The two patients who progressed while on therapy received R-CHOP but both did not responded and died. Stem-cells were collected after more than 2 cytapheresis in only 4 cases. To date, fifty-three patients (84%) out of 63 underwent ASCT. Response rate: in an intention to treat analysis, the ORR after 4 courses of R-DHAP is 92% including 32 patients who reached CR and 20 patients who reached CRu according to Cheson criteria (JCO 1999). Taken together, the CR/CRu rate after 4 courses of R-DHAP is 82.5%. Conclusion: R-DHAP alone is feasible with limited toxicity. This result of the ongoing LyMa trial confirms the major impact of HA in MCL untreated patients showing CR/CRu rates that are superior to those usually obtained with R-CHOP alone or alternating protocols such as R-CHOP/R-DHAP. FDG-PET analysis and response at the molecular level after 4 RDHAP courses have also been analyzed. Disclosures: Off Label Use: velcade is of label in France for the treatment of mantle cell lymphoma. Tilly:Amgen: Honoraria.

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma

2009 ◽  
Vol 145 (3) ◽  
pp. 344-349 ◽  
Author(s):  
Thomas M. Habermann ◽  
Izidore S. Lossos ◽  
Glen Justice ◽  
Julie M. Vose ◽  
Peter H. Wiernik ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Response Rate ◽  
High Response ◽  
Mantle Cell

Reduced Intensity Allogeneic Transplantation for Non-Hodgkin’s Lymphoma: Extended Follow-Up of an Alemtuzumab-Containing Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 401-401 ◽  
Author(s):  
Kirsty J. Thomson ◽  
Emma C. Morris ◽  
Don Milligan ◽  
Gordon Cook ◽  
Jim Cavet ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
Low Grade ◽  
High Grade ◽  
Reduced Intensity Conditioning ◽  
Mantle Cell ◽  
Reduced Intensity

Abstract Allogeneic transplantation with reduced intensity conditioning is increasingly being used in patients with non-Hodgkin’s Lymphoma (NHL) who fail standard therapy. We report extended follow-up on 121 patients with NHL, who underwent allogeneic transplantation with reduced intensity conditioning at 8 UK centres. Conditioning was with fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (60–120mg). Cyclosporin A was administered at 3mg/kg from day-1, and stem cell source was bone marrow or PBSC. Diagnoses were in 3 categories: low grade follicular NHL (n=50), mantle cell lymphoma (n=21), and high-grade NHL (n=50, including transformed low grade disease n=15). Donors were HLA-matched siblings in 75 (62%), and unrelated in 46 (38%), of whom 18 were HLA-mismatched at up to 3/10 loci. 48% of patients had failed previous autologous transplantation. Median follow-up was 35 months (1–78). For the group with low grade follicular NHL (n=50), estimated overall survival (OS) was 76% at 1yr and 67% at 4yrs, and non-relapse mortality (NRM) was 16% at 4yrs. Disease relapse or progression occurred in 12 patients, of whom 8 received donor lymphocyte infusions (DLI), with responses in 6. Current progression-free survival (cPFS) is 68% at 4yrs. For the group with mantle cell lymphoma (n=21), estimated OS was 83% at 4yrs, NRM was 11% at 4yrs and relapse or progression occurred in 6 patients. Three patients received DLI, with non-sustained responses in 2. Current PFS is 43% at 4yrs. For high-grade NHL (n=50), estimated OS was 52% at 1yr and 45% at 4yrs. Prior autologous transplantation was common in this group (72%), and NRM was higher at 34% at 1yr and 40% at 4yrs. Progression/relapse occurred in 15 patients, of whom 10 received donor lymphocytes, with responses in 5. Current PFS is 48% at 1yr and 43% at 4yrs. These results, from patients who were often heavily pre-treated, including having failed autologous transplantation, provide encouraging evidence to support the application of reduced intensity allogeneic transplants in NHL. NRM in low grade follicular or mantle cell lymphoma is low, consistent with the use of T cell depletion, and graft-versus-lymphoma effects can be induced with DLI in a subset of cases. The data in follicular lymphoma, in particular, supports consideration of this therapy earlier in the disease. In high-grade disease, NRM appears to be higher, but durable remissions are attainable in a proportion of patients.

Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology, a high proliferative state, and p53 overexpression

2002 ◽  
Vol 199 (1) ◽  
pp. 90-97 ◽  
Author(s):  
Joseph D Khoury ◽  
L Jeffrey Medeiros ◽  
George Z Rassidakis ◽  
Timothy J McDonnell ◽  
Lynne V Abruzzo ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
High Grade ◽  
P53 Overexpression ◽  
Mantle Cell

Multimodal Dose Dense Therapy for Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1163-1163
Author(s):  
Sam O. Wanko ◽  
Jon P. Gocherman ◽  
Joseph O. Moore ◽  
Carlos Decastro ◽  
Robert Prosnitz ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Induction Therapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Mantle Cell ◽  
Dose Dense

Abstract BACKGROUND: Mantle cell lymphoma (MCL) typically has a poor outcome with overall survival of only 3–4 years. Higher treatment response and event-free survival has been demonstrated with aggressive high dose chemotherapy followed by autologous hematopoietic stem cell support, though long term cure rates remain unclear(Dreger P. Hematol J. 2000;vol.2). Modest response rates have also been reported with the monoclonal antibody (MoAb) rituximab and ALEMTUZUMAB (Foran, JM. JCO 2000; vol. 2. Faderl S. Blood 2003; vol. 9). We therefore combined dose-dense therapy with MoAbs to explore response rate and event free survival (EFS) in mantle cell lymphoma. The strength of this trial design is ability to follow all patients from induction chemotherapy through high dose therapy and transplant in order to gauge clinical outcome on all enrolled patients, not just the subpopulation who is able to proceed to high dose therapy. PATIENTS AND METHODS: Induction therapy consisted of 1 cycle of high dose cytarabine (3gm/m2 IV over 1 hour Q12H for 8 doses), mitoxantrone (10mg/m2 daily for 3 days), and ALEMTUZUMAB 30mg IV 3 times a week for 6 weeks with growth factor support. All responding patients were mobilized with cyclophosphamide 4gm/m2 and G-CSF 10 mcg/kg/day and/or bone marrow harvest. The transplant preparative regimen was carmustine 15mg/kg over 2 hours day -6, etoposide 60mg/kg over 4 hours day -4, and cyclophosphamide 100mg/kg over 2 hours day -2 followed by autologous reinfusion on day zero. Consolidation was given with rituximab 375mg/m2 weekly for 4 doses at 6 weeks and 6 months post transplant. RESULT: 9 patients with advanced disease (7 stage IV, 1 stage III, 1 stage IIA) and median age of 60 (48 – 65 years) have been accrued and treated since February 2003. Four were newly diagnosed and 5 had relapsed/refractory disease. Seventy eight percent (7/9) had complete response and 22% (2/9) had partial response (PR) following induction therapy. One patient had severe infection after induction and was unable to proceed to transplant. Another had constitutional decline preventing further therapy and each died within 4 months of withdrawal from the protocol. Both had relapse/refractory disease at accrual. The remaining 7 patients proceeded to the transplant phase. With a median follow-up of 7 months (range 3–16 months), all 7 patients remain in CR for 1 –16 months. Significant induction therapy toxicity included neutropenia in all 9 patients with average duration of 10.7 days, non-disseminated CMV reactivation in 44% of patients, one overwhelming fungal infection, and one patient with delay in engraftment. Figure Figure CONCLUSION: Our preliminary data show a high induction and transplant phase completion rate, manageable toxicity, and excellent overall response rate in this group of elderly patients with advanced disease. Larger numbers of patients and longer follow-up is needed to confirm these promising results.

Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 129-129 ◽  
Author(s):  
Thomas Witzig ◽  
Susan Geyer ◽  
Irene Ghobrial ◽  
David Inwards ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Median Time ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Pi3k Pathway ◽  
Mantle Cell ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2510-2510
Author(s):  
Gaël Roué ◽  
Mónica López-Guerra ◽  
Pierre Milpied ◽  
Patricia Pérez-Galán ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Mantle Cell ◽  
P53 Status

Abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.

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