Multimodal Dose Dense Therapy for Mantle Cell Lymphoma.

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 > 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.

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Multimodal Dose Dense Therapy for Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1163.1163 ◽

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.

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

Blood ◽

10.1182/blood.v112.11.3597.3597 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3597-3597 ◽

Cited By ~ 2

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.

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Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Annals of Oncology ◽

10.1093/annonc/mdu264 ◽

2014 ◽

Vol 25 ◽

pp. iii83-iii92 ◽

Cited By ~ 99

Author(s):

M. Dreyling ◽

C. Geisler ◽

O. Hermine ◽

H.C. Kluin-Nelemans ◽

S. Le Gouill ◽

...

Keyword(s):

Clinical Practice ◽

Mantle Cell Lymphoma ◽

Clinical Practice Guidelines ◽

Practice Guidelines ◽

Cell Lymphoma ◽

Newly Diagnosed ◽

Mantle Cell

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Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽

10.1182/blood-2020-133298 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Mats Jerkeman ◽

Martin Hutchings ◽

Riikka Räty ◽

Karin Fahl Wader ◽

Anna Laurell ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Molecular Remission ◽

Mantle Cell ◽

Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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Outcomes of Autologous and Allogeneic BMT for Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.901.901 ◽

2004 ◽

Vol 104 (11) ◽

pp. 901-901 ◽

Cited By ~ 1

Author(s):

Yvette L. Kasamon ◽

Richard J. Jones ◽

Louis F. Diehl ◽

Hassan Nayer ◽

Michael J. Borowitz ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

First Line Therapy ◽

Mantle Cell ◽

First Remission ◽

Total Body ◽

Induction Failure ◽

Relapsed Disease

Abstract To evaluate BMT outcomes in patients (pts) with newly diagnosed or relapsed mantle cell lymphoma, 58 consecutive pts were selected through the BMT registry at Johns Hopkins. Flow cytometric and immunohistochemical features were confirmed. Fifty-four pts (88%) had stage III or IV disease and 39 (67%) had documented bone marrow involvement at diagnosis. First-line therapy was CHOP +/− rituximab in 71% and was fludarabine-based in 17%. Thirty-seven pts (64%) were transplanted after first partial or complete remission, 14 pts (24%) after one or more relapses, and 12% after primary induction failure (PIF). Median age at BMT was 55 years. Thirty-eight pts (66%) received autologous (auto) BMT, 19 pts (33%) allogeneic (allo) BMT, and 1 pt syngeneic BMT. Preparative regimens in all but 1 case consisted of cyclophosphamide plus busulfan or total body irradiation. The estimated 3-year event-free survival (EFS) following BMT was 51% (95% CI, 35–65%), probability of relapse 31% (17–51%), and overall survival 59% (42–73%). Median follow-up is 16 months (range < 1 month to 79 months) for all pts and 23 months for surviving pts. Twelve relapses were documented, 8 after auto BMT. Four auto pts and 1 allo pt are alive with relapsed disease, and 3 auto pts developed MDS or AML. Actuarial EFS at 3 years was 57% (CI 35–74%) after auto BMT and 37% (17–57%) after allo BMT. Actuarial relapse rate at 3 years was 34% following auto BMT and 19% following allo BMT. On multiple regression analysis, BMT after one or more relapses (HR 3.0, CI 1.2–7.4, P = 0.02), PIF (HR 5.4, CI 1.9–15.4, P = 0.002), and allo BMT (HR 3.0, CI 1.3–6.8, P = 0.007) predicted an inferior EFS; Figure Figure whereas PIF and residual bone marrow involvement independently predicted relapse. Notably, however, EFS curves were not statistically different for auto and allo BMT performed in first remission, with the 3 year EFS approaching or equaling 70%. Figure Figure The benefit of BMT for mantle cell lymphoma is thus most apparent when performed in first remission. While the comparative efficacy of auto and allo BMT remains to be determined, allo BMT warrants continued study especially early in the disease course.

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

Blood ◽

10.1182/blood.v112.11.3050.3050 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3050-3050 ◽

Cited By ~ 3

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.

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

Blood ◽

10.1182/blood.v118.21.2681.2681 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2681-2681 ◽

Cited By ~ 1

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

Blood ◽

10.1182/blood.v110.11.1363.1363 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1363-1363 ◽

Cited By ~ 1

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.

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Rituximab-EPOCH, an Efective Front-Line Therapy for Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.4490.4490 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4490-4490

Author(s):

Andres Palacios ◽

Andres Lopez ◽

Antonio Salar ◽

Marta Cervera ◽

Merche Gironella

Keyword(s):

Prospective Study ◽

Mantle Cell Lymphoma ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Complete Response ◽

Newly Diagnosed ◽

Line Therapy ◽

Mantle Cell ◽

Grade Iii

Abstract Introduction: Mantle-cell lymphoma accounts for 3–10% of non-Hodgkin’s lymphomas, with a median survival not exceeding of 3–4 years and its remains incurable with conventional therapy. CHOP plus Rituximab can induce a molecular complete response in 36% of patients. More aggressive combinations, as Hyper CVAD achieved an overall response rate of 97% with 87 of complete response, data no further confirmed in other studies in which Hyper-CVAD together with Rituximab achieve an overall response rate of 62.5%, with 33% of complete responses (CR). Being toxicity high mainly in elderly patients. Infusional chemotherapy combinations have shown efficacy in mantle-cell lymphoma (as VAD). Based this premise and in the efficacy of infusional R-EPOCH in aggressive lymphomas (DLBCL and PMBCL) we have conducted a compassionate prospective study of non-adjusted infusional EPOCH-R in patients with mantle -cell lymphoma as first-line therapy. Aim: To evaluate the clinical activity and toxicity of non-escalated infusional EPOCH-R as upfront therapy in patients newly diagnosed of mantle-cell lymphoma. Patients and methods: Herein, 12 patients of an ongoing compassionate prospective study in newly diagnosed patients with mantle-cell lymphoma are reported. EPOCH-R consisted on Rituximab 375 mg/m2 day 1, vincristine 0.4 mg plus doxorubicine 40 mg/m2 plus etoposide 50 mg/m2 days 1 to 4 in four day continuous infusion, cyclophsphamide 750 mg/m2 day 5, and prednisone 60 mg/m2 for 5 days, repeated every 21 days if feasible for 6 cycles. The median age of 65 yrs (range, 49–76). 50% of patients were males. 91% of patients presented with an Ann Arbor stage III–IV, high LDH in 50% of cases, leukemic status in 66.6%, Bone Marrow involvement in 66.6% and ECOG <2 was present in 91% of the cases. Results: The response rate to EPOCH-R was 100% with 91% complete response (11 out of 12 patients). Neutropenia grade III–IV was observed in 16% of cases and anemia grade III–IV in 16% of cases. One case of neutropenic fever and two cases of grade III diarrhoea. Conclusions: These preliminary results suggest that EPOCH-R is an effective as other more aggressive combinations and probably with less toxicity profile. More experience and longer follow-up is warranted to confirm this initial appealing experience.

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Cladribine Plus Rituximab Is An Effective Therapy for Newly Diagnosed Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v116.21.4910.4910 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4910-4910

Author(s):

Stephen Spurgeon ◽

Talia Pindyck ◽

Marc M Loriaux ◽

Craig Okada ◽

Kamal Abbi ◽

...

Keyword(s):

Complete Remission ◽

B Cell ◽

Initial Treatment ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Treatment Strategies ◽

Newly Diagnosed ◽

Mantle Cell

Abstract Abstract 4910 Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is incurable with standard chemotherapy and remains a therapeutic challenge. Despite improved outcomes in MCL there is no consensus on the best initial treatment. Options vary from aggressive treatment strategies that incorporate multi-agent induction chemotherapy and consolidative transplant to less intensive treatment strategies that utilize alkylators, purine nucleoside analogues, and the monoclonal antibody rituximab. Although, higher response rates have been seen with aggressive approaches, their impact on overall survival is not yet fully appreciated and many patients are not candidates for such approaches. Thus, finding less intensive induction regimens is imperative. The combination of rituximab plus cladribine has shown activity across a number of B-cell malignancies and the NCCN treatment guidelines currently include this regimen for the initial treatment of MCL; noting that there are few data available to substantiate this recommendation. The largest prospective experience (n=29) with R-cladribine for the initial treatment of MCL comes from the North Central Cancer Group. They reported an overall response rate (ORR) of 66% with a 52% complete remission (CR) rate and a 2 year progression free survival (PFS) of 43%. Given its therapeutic potential and increasing popularity, more data are needed to verify the benefits of the R-cladribine regimen. Therefore, to explore the role of R-cladribine in the treatment of newly diagnosed MCL, we performed a retrospective chart review of patients with newly diagnosed MCL treated with R-cladribine. Methods: We reviewed the charts of 31 patients with newly diagnosed MCL initially seen at two university hospitals and at an associated VA that were treated with R-cladribine. One patient had been previously treated with 2 cycles of R-CHOP;, all other patients were untreated. All patients had measurable disease and follow up imaging (CT and/or PET/CT scans) before and at the completion of therapy. Post treatment bone marrow biopsies were not available for all patients. Chemotherapy included: cladribine 5mg/m2 given over two hours on days 1–5; and rituximab given on days 1, 8, 15, and 22 with the first cycle and then on day 1 with subsequent cycles. Each cycle was 28 days for up to a total of 6 cycles. Patients with an initial response received maintenance rituximab. Results: The median age of our cohort was 67 years (48-86) with 42% of patients ≥ 65 years. All patients had advanced stage disease (stage ≥ 3) and the majority of patients had poor risk disease. For example, 20/31 (65%) of patients had high FLIPI (≥ 3) and11/31 (37%) had high MIPI (≥ 6). Of the 24 patients in whom beta2-microglobulin was available, 11 (46%) had levels ≥ 3.5 mg/L. The overall response rate (ORR) was 87% with 19/31(61%) of patients achieving a complete remission (CR/CRu). At a median follow up of 21.5 months (2-85 months) the 2 year PFS rate is 65% and the OS rate is 74%. For those subjects achieving a CR/CRu with a median follow up of 23 months, 1/19 (5.3%) has relapsed. No significant trends were seen regarding response rate and pre-treatment disease defining parameters including Ki67, beta2-microglobulin, FLIPI, or MIPI. However, CR was associated with improved survival (p = <.0001) while high MIPI was associated with worse survival (p=0.0317). There was one toxic death (neutropenic sepsis) related to treatment. Conclusion: The combination of rituximab plus cladribine appears to be an effective initial therapy in MCL. The higher response rates seen in this series may be the result of patient selection and/or increased rituximab exposure. Rituximab maintenance may also be an important component of ongoing disease control in responding patients. These data support the ongoing evaluation of rituximab plus cladribine in combination with novel agents. Prospective single arm studies incorporating R-cladribine with other novel agents such as vorinostat, bortezomib, or temsirolimus are ongoing. Disclosures: No relevant conflicts of interest to declare.

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