Expression of eukaryotic initiation factor 4E predicts clinical outcome in patients with mantle cell lymphoma treated with hyper-CVAD and rituximab, alternating with rituximab, high-dose methotrexate, and cytarabine

PURPOSE Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. PATIENTS AND METHODS Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants. RESULTS Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. CONCLUSION The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.

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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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Proliferation predicts failure-free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabine

Cancer ◽

10.1002/cncr.24141 ◽

2009 ◽

Vol 115 (5) ◽

pp. 1041-1048 ◽

Cited By ~ 24

Author(s):

Mar Garcia ◽

Jorge E. Romaguera ◽

Kedar V. Inamdar ◽

George Z. Rassidakis ◽

L. Jeffrey Medeiros

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Free Survival ◽

Dose Methotrexate ◽

Mantle Cell

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High Rate of Durable Remissions After Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus High-Dose Methotrexate and Cytarabine

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.1825 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7013-7023 ◽

Cited By ~ 388

Author(s):

Jorge E. Romaguera ◽

Luis Fayad ◽

Maria A. Rodriguez ◽

Kristine R. Broglio ◽

Frederick B. Hagemeister ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Survival Rates ◽

Myelogenous Leukemia ◽

High Dose ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Mantle Cell ◽

Overall Survival Rates

Purpose To determine the response, failure-free survival (FFS), and overall survival rates and toxicity of rituximab plus an intense chemotherapy regimen in patients with previously untreated aggressive mantle-cell lymphoma (MCL). Patients and Methods This was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of six to eight cycles. Results Of 97 assessable patients, 97% responded, and 87% achieved a complete response (CR) or unconfirmed CR. With a median follow-up time of 40 months, the 3-year FFS and overall survival rates were 64% and 82%, respectively, without a plateau in the curves. For the subgroup of patients ≤ 65 years of age, the 3-year FFS rate was 73%. The principal toxicity was hematologic. Five patients died from acute toxicity. Four patients developed treatment-related myelodysplasia/acute myelogenous leukemia, and three patients died while in remission from MCL. A total of eight treatment-related deaths (8%) occurred. Conclusion Rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine is effective in untreated aggressive MCL. Toxicity is significant but expected. Because of the shorter FFS concurrent with significant toxicity in patients more than 65 years of age, this regimen is not recommended as standard therapy for this age subgroup. Larger prospective randomized studies are needed to define the role of this regimen in the treatment of MCL patients compared with existing and new treatment modalities.

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Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma

British Journal of Haematology ◽

10.1111/j.1365-2141.2010.08228.x ◽

2010 ◽

pp. no-no ◽

Cited By ~ 10

Author(s):

Jorge E. Romaguera ◽

Luis E. Fayad ◽

Lei Feng ◽

Kimberly Hartig ◽

Pamela Weaver ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Mantle Cell Lymphoma ◽

Cell Transplantation ◽

Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Mantle Cell

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Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment

Hematology ◽

10.1182/asheducation-2016.1.437 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 437-445 ◽

Cited By ~ 16

Author(s):

Eva Hoster ◽

Christiane Pott

Keyword(s):

Clinical Outcome ◽

Mantle Cell Lymphoma ◽

Minimal Residual Disease ◽

Residual Disease ◽

Cell Lymphoma ◽

High Dose ◽

Clinical Relapse ◽

Cytotoxic Treatment ◽

Mantle Cell ◽

Minimal Residual

Abstract Despite the recent substantial improvement of clinical outcome in mantle cell lymphoma (MCL), resistance to immunochemotherapy and common relapses are challenges for long-term tumor control. The assessment of minimal residual disease (MRD) by real-time quantitative polymerase chain reaction has emerged as a widely feasible and standardized tool for direct assessment of therapy-induced reduction of tumor burden and regrowth after cytotoxic treatment in MCL, with much improved sensitivity compared with conventional staging procedures. Several studies have shown that intensification of initial treatment, which has resulted in improved clinical outcome, is immediately reflected in higher molecular remission rates; they have also shown that high-dose consolidation might not be able to compensate for less intensive induction regimens. Persistence or reappearance of MRD in clinical remission proved to be highly predictive for imminent clinical relapse associated with shorter overall survival. Therefore, the investigation of novel MRD-guided treatment strategies aimed at early eradication of MRD and pre-emptive treatment of molecular relapse seems warranted. Furthermore, the integration of MRD assessment into clinical response criteria could result in a more specific and potentially earlier end point for treatment efficacy. New technical developments such as high-throughput sequencing will further enhance the wide applicability of MRD detection in MCL.

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Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial

Bone Marrow Transplantation ◽

10.1038/s41409-020-01198-2 ◽

2021 ◽

Author(s):

Benoit Tessoulin ◽

David Chiron ◽

Catherine Thieblemont ◽

Lucie Oberic ◽

Kamal Bouadballah ◽

...

Keyword(s):

Disease Control ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Autologous Transplantation ◽

Prospective Trial ◽

High Dose ◽

Mantle Cell ◽

High Dose Cytarabine

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Impact of Mantle Cell Lymphoma Contamination of Autologous Stem Cell Grafts on Outcome After High-Dose Chemotherapy

Cancers ◽

10.3390/cancers13112558 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2558

Author(s):

Malte Roerden ◽

Stefan Wirths ◽

Martin Sökler ◽

Wolfgang A. Bethge ◽

Wichard Vogel ◽

...

Keyword(s):

Stem Cell ◽

Mantle Cell Lymphoma ◽

Clinical Decision Making ◽

Cell Lymphoma ◽

High Dose Chemotherapy ◽

High Dose ◽

Hematopoietic Stem ◽

Increased Risk ◽

Mantle Cell ◽

Autologous Grafts

Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL.

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Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement

Cancers ◽

10.3390/cancers13122945 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2945

Author(s):

Mélanie Mercier ◽

Corentin Orvain ◽

Laurianne Drieu La Rochelle ◽

Tony Marchand ◽

Christopher Nunes Gomes ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Skeletal Involvement ◽

Large B Cell Lymphoma ◽

Dose Methotrexate ◽

The Impact ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

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