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.

Rituximab and Stem Cell Transplantation Produces Durable Remissions in Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1390-1390
Author(s):  
Francisco J. Capote ◽  
M. J. Pascual ◽  
E. Gonzalez-Barca ◽  
J. M. Bergua ◽  
A. Jimenez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Mantle Cell Lymphoma ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell

Abstract Introduction: Mantle cell lymphoma (MCL) is a CD20+ malignancy comprising up 5% of non-Hodgkin’s lymphomas, and has a poor prognosis under standard chemotherapy. The HyperCVAD-M/A regimen (fractionated high-dose cyclophosphamide, vincristine, doxorubicin and prednisolone alternated with methotraxate and cytarabine) has yielded encouraging results when combined with autologous stem cell transplantation (ASCT) in MCL, with 5-year failure-free survival of 54% and overall survival 72%. In an effort to improve these results further, we have combined rituximab in vivo purging and post-transplant consolidation with HyperCVAD-M/A plus ASCT. Methods: Patients aged <65 years with previously untreated or relapsed MCL were treated with four courses of HyperCVAD-M/A followed by four once-weekly doses of rituximab 375mg/m2 as purging prior to stem cell mobilization and harvesting, high-dose chemotherapy (ICT-CY or BEAM), stem cell reinfusion and four further doses of rituximab immunotherapy post-transplant. Results: Of the 34 patients enrolled so far, 15 (12 male, 3 female; 12 previously untreated) have been transplanted. The median age was 52 years (range 47–63 years). After the final post-ASCT immunotherapy all 15 patients were in clinical complete remission. With a median follow-up of 30 months from diagnosis (range 7–52 months), 14 patients remain alive with 13 in first complete remission. One patient died 15 months post-ASCT without evidence of disease recurrence. Kaplan-Meier estimates of 4-year overall and event-free survival are 93.3% and 86.6% respectively. Conclusions: This approach seems safe and feasible and produces durable remissions; longer follow-up of a more patients will be required to assess the effect of the procedure on survival.

Rituximab Plus Hypercvad Alternating with High Dose Methotrexate and Cytarabine for Patients with Newly Diagnosed Mantle Cell Lymphoma. A Multicenter Trial from GISL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3050-3050 ◽  
Author(s):  
Francesco Merli ◽  
Stefano Luminari ◽  
Fiorella Ilariucci ◽  
Caterina Stelitano ◽  
Mario Petrini ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Hematological Toxicity ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Dose Methotrexate ◽  
Mantle Cell

Abstract BACKGROUND. Rituximab plus HyperCVAD alternating with High Dose Methotrexate and Cytarabine (R-HCVAD) has been tested in patients with newly diagnosed Mantle Cell Lymphoma (MCL) with promising results (Romaguera et al. JCO 2005). In 2005 the Gruppo Italiano Studio Linfomi (GISL) started a phase II multicenter study investigating clinical activity and toxicity of R-HCVAD in a similar group of patients. PATIENTS AND METHODS. To be included in the trial patients must have histologically confirmed diagnosis of MCL, be younger than 70 years, have adequate organ function. Chemotherapy consisted of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicine, and dexamethasone(considered one cycle) alternating every 21 days with rituximab plus high dose methotrexate-cytarabine (considered one cycle) for a total of eight cycles per the MD Anderson protocol. Patients with baseline PCR positivity for t(11;14) on bone marrow (BM) had to perform PCR assessment of BM at evaluation of response and during follow-up. Only patients achieving partial response (PR) were to be addressed to HDC followed by ASCT. RESULTS. Thirty-two patients were enrolled. There were 23 males and 9 females; median age was 54 yrs (29 to 66), 80% were in stage IV, 50% and 71% had Gastrointestinal (GI) and BM involvement, respectively; PCR for t(11;14) was positive on BM in 51% of cases. Seven patients did not complete treatment due to toxicity; of these, two patients died (one with septic shock at cycle 1, one with pulmonary aspergillosis at cycle 4), one patient had thrombosis of central line extended to right atrium at cycle 1, one had grade IV skin reaction at cycle 3, one had a severe pneumonia at cycle 1, two had persistent grade IV hematological toxicity after cycle 1 and 5, respectively. All patients had grade III–IV hematological toxicity. Response was assessed in 17 patients with 16 CR and 1 PR. PCR for t(11;14) negativity on BM was achieved in 4/9 patients after cycle 4 and in 8/9 after cycle 8. After a median follow-up of 24 months 1 patient progressed at 6 months and 1 patient relapsed after 26 months of follow-up. Two-year Failure Free Survival (FFS) was 75% (IC95% 53 to 87) and 2 year Disease Free Survival was 93%(IC95% 59–99). CONCLUSIONS. Though longer follow-up is needed R-HCVAD regimen used in our multicenter setting confirmed high efficacy in terms of response (both clinical and molecular) and FFS. However the regimen was associated to a severe toxicity profile that caused treatment discontinuation in several patients and that may limit its use in the clinical setting.

Phase-2 Study of R-MACLO-IVAM-T in Newly Diagnosed Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1363-1363 ◽  
Author(s):  
Izidore S. Lossos ◽  
Francine Colleman ◽  
Gail Walker ◽  
Maricer Escalon ◽  
Joseph Rosenblatt ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Phase 2 Study ◽  
Mantle Cell

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable sub-type of B-cell non-Hodgkin lymphoma (NHL) characterized by brief progression-free survival (PFS) and median overall survival (OS) of only 3–4 y. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a great need for novel treatment strategies for this lymphoma entity. Method: We conducted a phase-2 study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO;14;925, 1996). Eligible patients had a confirmed diagnosis of MCL using WHO criteria, age 18–75 y, ECOG PS ≤2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures including colonoscopy. Prior to initiating thalidomide, subjects were enrolled into S.T.E.P.S.® program. Therapy consisted of R-MACLO (rituximab 375 mg/m2 IV on d 1, Adriamycin, 45 mg/m2 IV on d 1, cyclophosphamide, 800 mg/m2 IV on d 1 and 200 mg/m2/d on d 2–5, vincristine, 1.5 mg/m2 on d 1 and d 8 capped to 2mg, methotrexate, 1.2 g/m2 IV on d 10 IV over 1 h followed by 5.52 g/m2 over 23 h followed by leucovorin 36 h later. G-CSF was begun on d 13. When ANC was >1.5x10e9/L R-IVAM was begun including rituximab, 375 mg/m2 IV d 1, cytarabine, 2.0 g/m2 IV every 12 h on d 1 and 2, ifosfamide, 1.5 g/m2 d 1–5 with mesna and etoposide, 60 mg/m2 d 1–5. Therapy was repeated 14 d after hospital discharge. After recovery from cycle-2 subjects were re-staged and responses assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide, 200 mg/d until lymphoma-recurrence or toxicity. Results: 18 subjects enrolled; 17 are evaluable. Median age was 59 y (range, 44–73y), all had ≥stage-3 MCL with bone marrow involvement in 15 and gastrointestinal involvement in 9. Distribution according to IPI: 0–1 factor, 2; 2 factors, 7; 3 factors, 6; and ≥4 factors, 3. 16 subjects had diffuse variant and 2, blastic variant. 14 subjects completed the 4 cycles of therapy; the therapy was stopped after 2 and 3 cycles, respectively, in the remaining two patients. 1 subject died of septicemia on d 8 of first cycle. All subjects completing ≥1 cycle achieved CR. No subject relapsed and 15 are alive with a median follow-up of 18 mo (range, 4–40 mo). One patient died at 38m from non-small cell lung cancer diagnosed 19m post MCL diagnosis. Common severe toxicities were grade-3–4 neutropenia, thrombocytopenia and anemia in 48%, 21% and 24% of R-MACLO cycles and in 81%, 84% and 40% of R-IVAM cycles. There were 10 bacteremias in 65 cycles 9 of which were after R-IVAM therapy. 5 episodes of reversible grade-1–2 renal toxicity occurred after methotrexate. 5 subjects receiving thalidomide had dose-reductions because of neutropenia. Conclusions The R-MACLO-IVAM-T therapy results in a high overall response rate with 100% CR and no relapses at median follow-up of 18 months. The contribution of each element of the regimen to this outcome requires study. Further clinical trials are suggested.

Immunochemotherapy (R-MCP) Is Not Superior to Chemotherapy (MCP) Alone in Advanced Mantle Cell Lymphoma - 42 Months Follow Up Results of the OSHO 39 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4474-4474
Author(s):  
Michael Herold ◽  
Antje Haas ◽  
Stephanie Srock ◽  
Sabine Neser ◽  
Kathrin H. Al Ali ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Randomised Trial ◽  
Progression Free Survival ◽  
Striking Difference ◽  
P Value ◽  
Free Survival ◽  
Mantle Cell

Abstract Introduction: Rituximab plus chemotherapy has been proved to be the standard in treating advanced follicular lymphoma. However in mantle cell lymphoma (MCL) the results are still controversial. Methods: In a prospective randomised trial (OSHO#39) we compared the efficacy and toxicity of MCP chemotherapy(mitoxantrone 8 mg/m2 d 1+2, chlormabucil 3x3 mg/m2 d 1–5 and prednisolone 25 mg/m2 d q 4 weeks)versus MCP plus rituximab (375 mg/m2 d -1) in advanced indolent lymphoma and mantle cell lymphoma. Here we present the results of the MCL subgroup (n=90) among the 358 randomised patients (FL, MCL, LPL). Study endpoints included overall and complete response rate (RR + CR), progression free survival (PFS), event free survival (EFS), overall survival (OS) and toxicities. Results: with a median follow-up of 43 months for the MCL subgroup we can provide relatively mature data. Concerning toxicities there was no striking difference between the treatment groups. The treatment results for the MCL patients are as follows: Conclusions: Concerning all end-points R-MCP is not superior to MCP chemotherapy alone in advanced mantle cell lymphoma. Immunochemotherapy is obviously not the solution for this poor prognosis lymphoma entity. Results R-MCP n=44 MCP n=46 p-value Response Rate 70,5% 63% .5074 Complete Responses 31,8% 15,2% .0822 PFS median 20,5 months 19 months .2482 PFS 42 months 31% 14% EFS median 19 months 14 months .1369 EFS 42 months 27% 11,5% OS median 56 months 50 months .4862 OS 42 months 60% 61%

Vorinostat (SAHA), Cladribine, and Rituximab in Previously Untreated Mantle Cell Lymphoma: Updated Results From a Phase I/II Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3675-3675 ◽  
Author(s):  
Stephen E Spurgeon ◽  
Kamal Sharma ◽  
David F. Claxton ◽  
Christopher W. Ehmann ◽  
Carla Gallagher ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Significant Activity ◽  
Free Survival ◽  
Mantle Cell ◽  
Upregulated Genes

Abstract Abstract 3675 Background: Mantle cell lymphoma (MCL) remains incurable and little consensus exists on the best standard initial therapy. However, improved understanding of disease biology has the potential to lead to novel treatment approaches including new perspectives on older drugs. For example, epigenetic modifications including altered DNA methylation and histone acetylation previously identified in MCL has provided the rationale for using the combination of a hypomethylating agent and a histone deactylase inhibitor. Here we show that agents with differing mechanisms have significant activity in previously untreated MCL. In addition to its cytotoxic effects in lymphoid malignancies, cladribine has hypomethylating properties. Vorinostat (SAHA) is a histone deacetylase inhibitor (HDACi) FDA approved in cutaneous T cell lymphoma with modest single agent activity in MCL. Preclinically, the combination of these agents has been shown to activate silenced genes. Since cladribine inhibits DNA methylation via a unique mechanism, it could also potentially inhibit histone methylation. We previously reported initial results of our Phase I/II trial combining SAHA, cladribine, and rituximab (SCR) for the treatment of B-cell non-Hodgkin's Lymphoma (NHL) [Spurgeon et al, ASH, 2012]. Here we present the updated results from the Phase II portion of the trial in the untreated MCL cohort including response rate, overall and progression free survival, and correlative studies. Methods: The achieved phase II starting dose was vorinostat 400 mg po (days 1–14) combined with cladribine 5mg/m2 IV (days 1–5), and Rituximab 375 mg/m2 IV (weekly × 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Response evaluation occurs after 2 cycles and at the completion of therapy. Responding patients are eligible to receive maintenance rituximab. Phase II eligibility includes relapsed NHL as well as previously untreated MCL. The primary outcome is response rate (ORR); secondary endpoints include progression-free survival (PFS) and overall survival (OS). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray, qRT-PCR and HELP methylation analysis. To evaluate the possible effects of SAHA metabolism on toxicity and response, UDP-glucuronosyltransferase 2B17 (UGT2B17) genotyping is also performed. This study continues to enroll patients. Results: 28 previously untreated MCL patients have been enrolled on the phase II portion of the study. 7 have not yet completed the planned 6 cycles; however, 26 patients have completed ≥ 2 cycles and are evaluable for response. The majority of responding patients have received maintenance rituximab. The overall response rate (ORR) is 100% (26/26) with 69% (18/26) achieving CR. Of those patients not attaining CR, 2 had blastic MCL and died, 3 have not yet completed active treatment, and 1 withdrew consent after two cycles. At a median follow up of 14.7 months (.07 – 25 months) 4 patients have relapsed and 3 have died. Of the relapsing patients, two had blastic MCL. None of the patients achieving a CR has relapsed. The estimated PFS curve (shown in the Kaplan-Meier curve below) did not reach the 0.5 level and therefore, median PFS could not be estimated. Toxicities were defined using CTCAE 4 and primarily include neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration. We found that cladribine hypomethylates DNA in vivo (8/8 pts) and inhibits histone methylation in vitro. There were no upregulated genes common to untreated leukemic MCL patients; however, a number of changes in gene expression were observed. For example, upregulated genes after treatment included DUSP2 (3 patients), FOXO3 (2 patients), NOXA1 (2 patients), CEBPb (2 patients) and p53 (3 patients). Conclusions: The SCR regimen has significant activity and shows epigenetic activity in previously untreated MCL. Initial follow up results are promising, especially in patients without blastic MCL who continue with maintenance rituximab. The SCR regimen should be studied further in NHL. Disclosures: Spurgeon: Merck : Research Funding. Off Label Use: vorinostat: off label use mantle cell lymphoma. Epner:Merck: Research Funding, Speakers Bureau.

Multimodal Dose Dense Therapy for Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5501-5501
Author(s):  
Sam O. Wanko ◽  
Jon P. Gockerman ◽  
Joseph O. Moore ◽  
Carlos de Castro ◽  
Louis Diehl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Newly Diagnosed ◽  
Mantle Cell ◽  
Dose Dense ◽  
Relapsed Disease ◽  
Cmv Reactivation

Abstract BACKGROUND: With the poor prognosis and outcome described in mantle cell lymphoma (MCL), there is a continuing need to explore treatment options that might overcome suspected underlying drug resistance and improve the current median survival of about 24 months. One strategy to overcome drug resistance has been the use of high dose therapy followed by autologous transplant. Newer agents such as the monoclonal antibodies (MoAb) rituximab and alemtuzumab which target CD20 and CD52 respectively have recently become available. We have therefore incorporated both a dose dense approach in combination with these antibodies to treat newly diagnosed and relapsed MCL patients. PATIENTS AND METHODS: A total of 16 patients have been enrolled since February 2003. Induction therapy consisted of 1 cycle of cytarabine 3gm/m2 IV 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 on day -6, etoposide 60mg/kg on day -4, and cyclophosphamide 100mg/kg on day -2 followed by autologous re-infusion. Consolidation was given with rituximab 375mg/m2 weekly for 4 doses at 6 weeks and 6 months post transplant. RESULT: Of the 16 patients, 12 had stage IV, 1 stage III, 3 stage IIA, and 1 stage I disease. The median age was 60 (48 66 years). Eight were newly diagnosed and 8 had relapsed disease with at least 2 prior chemotherapy treatments. In the induction phase, overall response rate was 94% (15/16 patients) with 73% complete response (CR) and 27% partial response (PR). Response rate were 100% and 88% in the newly diagnosed and relapsed patients respectively but CR was similar (75%) in both groups. Nine patients have been transplanted and one patient is awaiting transplant. Six patients were not transplanted due to death in 2 patients with relapsed disease at study entry, and one each due to progression of disease, prolonged cytopenias of &gt; 60days, mental status changes and inability to collect peripheral or bone marrow stem cell respectively. Among the transplanted patient, 78% (7/9) remain in CR with 2-year lymphoma progression free survival of 67% after a median follow-up of 487 days (range 175–787 days). Induction therapy toxicities included average neutropenia duration of 11.6 days and CMV reactivation of 50% that was equally distributed in the transplanted and non-transplanted patients. Peripheral stem cell collection was inadequate in 5 of the transplanted patients requiring bone marrow harvest. CONCLUSION: Our preliminary data continue to show a high induction response rate with majority of patients who are able to proceed to the transplant phase remaining free of lymphoma at 24 months. Toxicity was manageable although bone marrow harvest was needed to obtain adequate stem cells in majority of transplanted patients. While CMV reactivation was observed in half of the patients, its effect on the ability of subjects to complete the study and on survival appear to be minimal. Although a small study, multimodal dose dense strategy with maintenance MoAb for patients with mantle cell lymphoma is a promising strategy that needs to be confirmed in larger number of patients with prolonged follow-up.

Bortezomib, Thalidomide, and Dexamethasone as Induction Therapy for Patients with Symptomatic Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3605-3605 ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
Sagar Lonial
Keyword(s):  
Induction Therapy ◽  
Progressive Disease ◽  
Response Rate ◽  
Progression Free Survival ◽  
High Response Rate ◽  
High Dose ◽  
High Dose Therapy ◽  
Free Survival ◽  
One Year

Abstract The optimal induction regimen for patients with symptomatic myeloma who are eligible for transplantation is currently unknown. While thalidomide and dexamethasone is an effective regimen, it only has a 60 to 65% response rate and few complete responses (CR). Bortezomib based inductions have demonstrated a high response rate and an improved CR as well. Recently the IFM reported the initial results of the randomized bortezomib plus dexamethasone versus VAD induction followed by transplant, which demonstrated that fewer patients treated with bortezomib required tandem transplants. Wang et al reported a high induction response rate with the combination of BTD for only 2 cycles given over a 28 day cycle. Here we report our experience with the combination of BTD as induction therapy. 38 patients with symptomatic myeloma were treated with BTD as induction therapy. Patients received standard dose and schedule bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 with thalidomide at 100 mg/day, and 8 days of 40 mg dexamethasone every 21 days. The median age was 58 years (38–70) with 19 males. This was first line therapy for 29 patients, second line for 7 patients and 3rd line for 2. 12 patients had ISS stage 2 and 8 had ISS stage 3. The median β2M was 3.4 (1.66–41.89). Median creatinine was 1.1 (0.6–21.0). Nineteen patients had an IgG paraprotein, 6 an IgA, and 16 patients had light chain disease. The median number of cycles administered was 4 (2–8). Fifteen patients developed neuropathy of any grade. One patient developed grade 3 neuropathy. The overall response rate (CR, VGPR, plus PR) was 92%, with 58% of patients achieving a VGPR or better, and 21% of patients achieving an immunofixation negative CR. 1 patient had a minimal response and 2 patients had progressive disease (both patients presented with plasma cell leukemia). These two patients were treated with the combination of BTD with PACE chemotherapy. One of the two died from progressive disease and the other patient remains in complete remission after high dose therapy and autologous transplantation. 29 patients had consolidation therapy with high dose melphalan and autologous peripheral blood stem cell transplantation. Eight patients have collected stem cells without proceeding with immediate consolidation therapy. After a median follow up of 373 days, median progression free survival and overall survival have not been reached. One year overall survival is 97%. One year progression free survival is 87%. In conclusion, we report a very high response rate with a short course of bortezomib, thalidomide and dexamethasone with an acceptable toxicity profile. Follow up of patients in CR treated without high dose therapy and autologous transplant is in progress. Further studies of this active regimen are warranted.

High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3597-3597 ◽  
Author(s):  
Peter J Hosein ◽  
Daniel Morgensztern ◽  
Francine Coleman ◽  
Gail Walker ◽  
Maricer Escalon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Relapse Rate ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.

High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2681-2681 ◽  
Author(s):  
Anne W Beaven ◽  
David A. Rizzieri ◽  
Zachary Powell ◽  
Zhiguo Li ◽  
Peggy Alton ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Dose Dense ◽  
Large B Cell

Abstract Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

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