A Phase 2 Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Plus Rituximab in Newly Diagnosed, Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3698-3698
Author(s):  
Robert W. Chen ◽  
Leslie Popplewell ◽  
Paul Frankel ◽  
Tanya Siddiqi ◽  
Joel Conrad ◽  
...  
Keyword(s):  
Median Time ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Mantle Cell ◽  
Time To Treatment Failure ◽  
Indolent Lymphomas

Abstract Abstract 3698 Background: Follicular, marginal zone and mantle cell lymphomas are indolent lymphomas that tend to recur with decreasing intervals of remissions. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases. Single agent vorinostat has an overall response rate of 29% in all indolent lymphomas (47% in follicular lymphoma) with prolonged disease free survival. (Kirschbaum, JCO 2009) Preclinical data suggests enhanced activity for the combination of vorinostat plus rituximab. We report the clinical results of a phase II study of the combination of vorinostat plus rituximab. Methods: These are the updated results of our two-stage phase II study in patients with newly diagnosed, relapsed or refractory follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. Rituximab is given on day 1 of each cycle. CT scanning and/or FDG-PET are performed after every three cycles. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous autologous transplant is allowed. The primary endpoint was the overall response rate according to Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 26 eligible patients were accrued thus far. See Table 1 for baseline characteristics. Outcomes are available on 23 patients: the overall response (CR+PR) rate thus far is 35% (8/23) The CR rate for all patients is 30% (7/23). The response rate for untreated patients (5 FL, 1 MZL) is 66.6% (4/6, all CR). The other two patients remain on study with prolonged stable disease. The formal response rate thus far for relapsed/refractory patients is 23.5% (4/17). By histology, the response rate is 35% (7/19) for FL, 0/2 for mantle cell, 1/1 for MZL, and 0/1 for lymphoplasmacytic lymphoma. The median time to achieve CR is 12 months. Of the 7 patients who achieved CR, 3 have relapsed while off treatment and were retreated with vorinostat plus rituximab. 1 achieved CR and is 13 months into treatment, 1 achieved PR and is 23 months into treatment, while 1 transformed both to Hodgkin lymphoma and diffuse large B cell lymphoma (biopsy proven). The median time to treatment failure for patients achieving CR is 38 months, with 6 ongoing, including the two retreated patients (14, 27, 29, 29, 31, and 35 months). Of non-responders, 8 patients achieved stable disease for at least 9 cycles with one SD for 63+ cycles. The disease control rate for > 9 cycles (CR+PR+SD) is 69.6% (16/23). Five patients were taken off study for reasons other than progression (2 patients choice, 1 to transplant, 1 for concomitant medication violation, and 1 physician choice). The median time to treatment failure for all patients was 9 months (95% CI, 6 months, NR). Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug include neutropenia (n=1), asymptomatic thrombosis (n=4), and thrombocytopenia (n=2). Grade 3 possibly related toxicities include fatigue (n=7), hyperglycemia (n=3), dehydration (n=2), and one each of thrombocytopenia, neutropenia, anemia, hypophosphatemia, hypotension, pneumonia, diarrhea, diverticulitis, and syncope. The thromboses were nonclinical pulmonary embolism discovered incidentally on CT scan, and resulted in amending the study to include 40 mg enoxaparin as prophylaxis, resulting in no further thromboses identified. Conclusions: The combination of vorinostat with rituximab is well tolerated, and shows encouraging activity against newly diagnosed, as well as relapsed/refractory indolent lymphoma. Durable responses can be achieved. Extended treatment with this combination is feasible and well tolerated, and retreatment with this regimen is efficacious in previous responders who relapsed. Disclosures: Off Label Use: Use of vorinostat in combination with rituxan for indolent B cell lymphomas.

Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7532-7532 ◽  
Author(s):  
S. M. Ansell ◽  
S. M. Geyer ◽  
P. J. Kurtin ◽  
D. J. Inwards ◽  
S. H. Kaufmann ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Early Evaluation ◽  
Overall Response ◽  
Mantle Cell ◽  
Anti Tumor Activity

7532 Background: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. Temsirolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly temsirolimus at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (JCO 23 (23); 5347–56, 2005). Thrombocytopenia was frequently observed and was dose limiting. The current study tested whether low-doses (25mg) of temsirolimus could produce a similar overall response rate (ORR) with less toxicity. Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received temsirolimus 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. The goal was to achieve an ORR of at least 20%. Results: Twenty-nine patients were enrolled between March and August 2005. Twenty-two patients have completed therapy. One patient with a major protocol violation on cycle-1 and one ineligible patient were excluded, leaving 27 evaluable patients. The ORR was 41% (11/27), with 1 CR and 10 PRs. Early evaluation of TTP showed a median of 5.5 months (95% CI: 3.3–7.7) and the duration of response for the 11 responders was 6.2 months (95% CI: 3.6 to not yet reached). These results compare favorably with the 6.5 months and 6.9 months, respectively, found in previous trials that used 250 mg. The median dose delivered per month was 80 mg (range, 10–100 mg). Sixteen (59%) of patients required a dose reduction. The median time on treatment was 4.4 months (95% CI, 3.3–7.7). The incidence of grade 3 and 4 thrombocytopenia was 12% and 0%, respectively. One patient experienced grade 5 infection without neutropenia, which was considered unrelated to CCI-779. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL similar to the 250 mg dose. This study indicates that combinations of temsirolimus with other agents should be feasible. [Table: see text]

Phase II: Combination of cladribine, cyclophosphamide, mitoxantrone, rituximab (R-CCM) in patients with relapsed and refractory follicular and mantle cell lymphoma, results of a prospective study at Kitasato University

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18542-18542 ◽  
Author(s):  
Y. Suzuki ◽  
M. Danbara ◽  
M. Hayama ◽  
T. Togano ◽  
M. Ohsaka ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Hemorrhagic Cystitis ◽  
Single Agent ◽  
Left Ventricular ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade Iii

18542 Background: Indolent non-Hodgkin’s lymphoma (I-NHL) account for 20% of all of NHL in Japan, and they are increasing in number. More than 80% of the patients who achieve a complete remission with the initial treatment, will require salvage therapy. Recently, cladribine (2-CdA), a purine analogue is receiving much attention, because, even as a single agent, it has shown a high efficacy for I-NHL. The aim of our study was to determine the effectiveness and toxicity of combined chemotherapy consisting of 2-CdA, cyclophosphamide (CYP), mitoxantrone (MIT), rituximab (R-CCM) in the treatment of refractory or relapsed I-NHL. Methods: Patient eligibility criteria were: Previously treated patients with I-NHL, refractory or relapsed disease, no chemotherapy or irradiation within 4 weeks prior to the study, life expectancy of at least 3 months, age: 20–75, perfomance status of 0–3, adequate function ( bone marrow, liver, kidney, lung, heart) and written informed consent. The treatment regimen was: 2-CdA given at a dose of 0.09 mg/kg/day in a 2-h intravenous infusion from day 2–4, CYP 200 mg/m2/day from day 2–4, MIT 8 mg/m2/day on day 2 and rituximab 375 mg/m2/day on day .Primary end point was overall response rate. Results: 9 patients were enrolled, 7 (2 with mantle cell lymphoma, MCL; and 5 with follicular lymphoma, FL) were eligible. Mean Age was 63(51–72). The mean observation time was 121 days(47–314). Overall response rate (complete and partial) just after this therapy was 85.7%, one was progressive disease. One of PR one relapsed and died ten months after this regimen. The major toxicity was myelosuppression. Grade-III and -IV neutropenia was seen in 7 patients, grade-III thrombocytopenia in one and grade-III hemorrhagic cystitis in one, but all of them recovered from these toxicity. After the treatment, Grade-IV pneumonia and grade-III left-ventricular diastolic dysfunction was seen in the PD patient and passed away. Conclusions: the R-CCM is effective and safe in a combined regimen for relapsed and refractory I-NHL patients. We have just begun this new regimen, therefore, further investigations with larger population are warranted. No significant financial relationships to disclose.

Bortezomib, Rituximab, and Dexamethason (BORID) as Salvage Treatment in Relapsed/Refractory Mantle Cell Lymphoma: Sustained Disease Control in Patients Achieving a Complete Remission.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2578-2578 ◽  
Author(s):  
Johannes Drach ◽  
Hannes Kaufmann ◽  
Oskar Pichelmayer ◽  
Verena Sagaster ◽  
Sonja Holzer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Control ◽  
Mantle Cell Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Dose ◽  
Synergistic Activity ◽  
Overall Response ◽  
Mantle Cell

Abstract Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We therefore evaluated the activity and safety of B in combination with R and dexamethasone (BORID) in patients with relapsed and refractory MCL (phase II trial). Methods: A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) achieving a response received 4 additional doses of R as maintenance (every 8 weeks). Pts with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) were eligible. Results: We have completed enrollment of 16 pts (median age, 67 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6, prior rituximab in 88%; thalidomide in 50%; high-dose therapy in 31%; a fludarabine-containing regimen in 31%). Median time between start of frontline therapy and study inclusion was 42 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Overall response rate was 69% (11 of 16 pts), with 6 pts achieving a CR (38%; confirmed by PET-scan in 5 pts) and 5 pts reaching a PR. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. Remission status appeared to be associated with progression-free survival (PFS): Patients in CR had longer PFS (29+, 24+, 21+, 12+, 12, and 10+ months) compared to patients in PR (median 8.5 months, range 6 – 15). Conclusions: BORID has promising activitiy (69% overall response rate; CR rate 38%) and managable toxicity in this patient population with predominantly heavily pretreated MCL. Achievement of a CR emerged as an important factor for sustained disease control. Further evaluation of this regimen, in particular in pts at an earlier phase of the disease, is warranted.

Clinical Efficacy of the Rivbd Combination for Refractory/Relapsed (R/R) Mantle Cell Lymphoma (MCL) Patients: A Retrospective Study of the French Lysa Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1111-1111
Author(s):  
Caroline Régny ◽  
Sandra Malak ◽  
Guillaume Manson ◽  
Clementine Sarkozy ◽  
Aline Clavert ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Salvage Therapy ◽  
Older Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Background There is no standard treatment for R/R MCL that fail first line treatment. Non cross resistant regimens are usually used, which provided sometimes good overall response rate (until 93%) but with a minor disease control (PFS<2years). [1] The main objective of these salvage regimens is to bypass disease resistance, to obtain more profound ( deep or durable) response and to ensure, in younger patients, the option of performing autologous or allogenic stem cell transplantation. For older patients prolonging disease free survival is the aim. The new combination RiVBD (Rituximab-Bendamustine-Bortezomib-Dexametasone) has recently shown to be an effective regimen in frontline for eldery patients with a good tolerability profile (NCT 01457144). [2] Many French centers have also used this association for the R/R patients. Aim To explore the efficacy of the RiBVD regimen in the salvage therapy setting following failure of one, two or more prior treatments. Methods We proposed to all French LYSA partner centers a survey to retrospectively evaluate the efficacy of the RiBVD regimen in R/R MCL patients, regardless of prior treatments used. The RiBVD regimen comprises : Rituximab 375mg/sqm D1, Bendamustine 90mg/sqm D1 and D2, bortezomib 1,3mg/sqm D1, D4, D8, D11 and dexamethasone 40 mg D2. Analysis was performed in June 2016. Results From January 2012 to December 2015, 49 patients from 17 French hematological centers were recruited to the study. The median age was 72 years (50-91y) with 14 young (<65y) and 35 older patients (> 65y). Thirty eight cases presented with classic MCL variant and 11 had a blastoid variant. All patients but one were CD20+, CD5+, CD10- and were positive CYCLIN D1 expression and/or the t(11;14)(q13;q32). Eighteen patients presented a t(11;14) (q13;q32).The CYCLIN D1 negative patient had a t(11;14). Treatment history: Twenty seven patients received RiBVD in second line, 12 in third line and 10 patients after the third lines. Twenty two patients were refractory to their previous line and 27 were in relapse. Before RiBVD 44/49 patients (90%) had received high dose cytarabine, 3 Ibrutinib and 14 patients were intensified (11 at diagnosis, 3 in relapse). Efficacy: The global overall response rate (ORR) was 75% (37/49, 23 CR and 14 PR). For patients treated in 2nd line, the ORR was 85% (23/27, 16 CR and 7 PR), in 3nd line 58% (7/12, 4 CR and 3 PR), and 70% (7/10) for the others (3 CR and 4 PR). Young patients had an ORR of 64% (9/14, 8 CR, 2 RP) and elderly pts 77% (27/35, 15 CR, 12 PR). For relapsed and refractory pts the ORR was respectively 85% (23/27, 15 CR and 8 PR) and 63% (14/22 with 8 CR and 6 PR). For Classic and blastoid variants the ORR was 81.5% (31/38, 20 CR and 11 PR) and 54% (6/11, 3 CR and 3 PR) respectively. Note that 2/3 pts receiving RiBVD regimen post Ibrutinib failure, reached PR (n=2) and showed stable disease (n=1). Major toxicities were seen in 31 pts (63%) with grade 3/4 hematological toxicity in 22 pts, grade 3 neurotoxicity in 3 pts, grade 3/4 cardiotoxicity in 3 pts, grade 3/4 infectious complications in 8 pts, grade 4 fatigue in 3 pts and grade 3 digestive-tract or cutaneous toxicity in one pt each. At the update point, 17 pts had died, 15 for lymphoma progression, 2 for TRM while experiencing a CR (infectious and leukemia). The follow-up of the 32 surviving pts was 14.5 month. The median PFS was 9 months for the 49 pts. The PFS was statistically affected by the pathologic type (classic vs Blastoid, p=0.03), the number of prior treatment (one vs >one, p=0.04) and response to RiBVD (CR vs PR vs no response, p<0.0001 with a median PFS not reached for CR pts, 6 months for PR and 2 months for no response. The age (<65 vs >65) or the state (relapse or refractory) at the time of RiBVD had no impact on PFS. Conclusion The RiBVD regimen which shows remarkable efficacy in frontline treatment of elderly MCL pts, shows potential as a salvage therapy for refractory or relapsed MCL following cytarabine based treatment. This is particularly true for the 47% of patients achieving CR for which 2 years PFS was 71% regardless of their age. 1. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol 2016; 34: 1256-1269. 2. Gressin R, Callanan M, Daguindau N et al. Frontline therapy with the RiBVD regimen elicits high Clinical and Molecular Response Rates and long PFS in elderly patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II trial by the LYSA group. Blood 2014. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
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.

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

Blood ◽  
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.

Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma

2021 ◽  
Author(s):  
Preetesh Jain ◽  
Shuangtao Zhao ◽  
Hun Ju Lee ◽  
Holly A. Hill ◽  
Chi Young Ok ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Older Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Ki 67 ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

PURPOSE Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial ( NCT01880567 ). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

scholarly journals Efficacy and Survival in Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized, Controlled, Multicenter and Open-Labled Study with Ddgp Regimen Versus SMILE Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 463-463 ◽  
Author(s):  
Xinhua Wang ◽  
Lei Zhang ◽  
Xiangli Liu ◽  
Xin Li ◽  
Ling Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Overall Response Rate ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Overall Response

Background Extranodal NK/T cell lymphoma (ENKTL) is rare in western countries but rather common in Asia and South America, characterized with Epstein-Barr virus (EBV) infection. Patients with advanced stage (III/IV) ENKTL has a poor survival and low response to conventional CHOP-like chemotherapy, with a 5-year overall survival rate of only 30%. Retrospective study showed that SMILE regimen had a certain effect on ENKTL, but the toxicity limited its further clinical application. More effective treatment regimens are required to be explored for systematic, prospective, controlled, randomized clinical trials. Recently, studies revealed that asparaginase-based combination chemotherapy such as P-Gmox(Pegaspargase, Gemcitabine, Oxaliplatin)is effective in patients of ENKTL. However standard treatment for newly untreated advanced ENKTL is still controversial. We developed a refined chemotherapeutic DDGP (dexamethasone, cisplatin, gemcitabline, and peg-asparaginase) regimen and proceeded a prospective randomized, multicenter and open-label clinical trial to evaluate and compare the efficacy and safety of DDGP with SMILE regimen in patients with newly diagnosed stage III/IV ENKTL in January 2011. Based on the encouraging interim results in 2016(Li, L et al.Clin Cancer Res, 2016), we presented the final results of this clinical investigation (ClinicalTrials.gov, No. NCT01501149). Patients and methods: The study was initiated at 9 centers in China in January 2011. Patients aged 14-70 with newly diagnosed ENKTL in stages III/IV, and ECOG performance score of 0-2 were enrolled. According to a computer-generated randomization schedule, eligible patients were assigned either DDGP regimen (cisplatin 20 mg/m² on day 1-4; dexamethasone 15mg/m2 on d1-5; gemcitabine 800mg/m2 on d1,8; pegaspargase 2500 IU/m2 on d1; 21 days per cycle)or SMILE regimen (methotrexate 2g/m2 on d1; dexamethasone 40mg/m2 on d2-4; ifosfamide 1500mg/m2 on d2-4; L-asparaginase 6000 U/m2 on d3-9; etoposide 100 mg/m2 on d2-4; 21 days per cycle) for up to 6 cycles unless disease progression, unacceptable toxicity or patient rejection. Efficacy was evaluated every two cycles. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR) and overall survival (OS). In addition we compared the safety and tolerability between DDGP and SMILE regimens. The Kaplan-Merier method was used to evaluate for survival of freedom from events, and the log-rank test was used to evaluate differences among two groups. Results: A total of 87 eligible newly diagnosed advanced ENKTL patients were randomly assigned for the study and 80 patients were included into intention-to-treat population (40 patients in DDGP group and 40 patients in SMILE group). Data were collected from January 2011 to February 2019. Baseline characteristics of the two group patients were well balanced. At median follow-up of 41.5 months, the median PFS and OS in the SMILE group were 6.83 months and 75.2 months, respectively, while the median PFS and OS in the DDGP group have not been reached (Fig 1). The 3-year PFS rate and 5-year OS rate in DDGP group were higher than in SMILE group (56.6% vs. 41.8% for 3-year PFS, P=0.004; 74.3% vs. 51.7% for 5-year OS, P=0.02). No difference of the complete remission (CR) rate was observed between two groups, while overall response rate (ORR) in DDGP group was higher than in SMILE group (90.0% vs. 60.0%, p=0.002) (Table 1). More frequently 3/4 grade hematologic toxicities such as leucopenia and netropenia were observed in SMILE group than in DDGP group (p=0.022, p=0.015). Non-hematologic toxicities included elevated transaminase, mucositis and allergy were higher in SMILE group than in DDGP group(p=0.027, p&lt;0.001, p=0.024). Pancreatitis occurred in 2 patients in SMILE group, but not in DDGP group (Table 2). In addition, treatment-related deaths rate was up to 17.5% in SMILE regimen which was mainly caused by infection and hemorrhage due to bone marrow suppression. Such event was only 10% in DDGP regimen. Conclusion: DDGP regimen produced prolonged survival, better tolerability and safety than SMILE regimen in newly diagnosed advanced ENKTL. Disclosures No relevant conflicts of interest to declare.

Interferon Alpha-2B (IFN-a) Is an Effective Agent for the Treatment of Primary Cutaneous T- and B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2643-2643
Author(s):  
Marina P. Siakantaris ◽  
Marie-Christine Kyrtsonis ◽  
Tatiana Tzenou ◽  
Evangelia M. Dimitriadou ◽  
Maria N. Dimopoulou ◽  
...  
Keyword(s):  
T Cell ◽  
Side Effects ◽  
B Cell ◽  
Median Time ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Overall Response

Abstract Primary cutaneous lymphoma comprise a wide range of rare diseases of which the commonest T- cell subtypes include mycosis fungoides (MF), Sezary syndrome (SS) and peripheral T-cell lymphoma (PTCL) while follicle center cell lymphoma (FCL), diffuse large B-cell lymphoma (DLBL) and extranodal marginal zone B-cell lymphoma (MZL) represent the B-cell subtypes. The behavior of these diseases is different from nodal NHL and it has been shown that IFN-a can produce long-lasting remissions in early stages MF. On the contrary, there are no reports on the efficacy of IFN- a for primary cutaneous B-cell lymphomas (CBCL). The purpose of this study was to present our experience on IFN -a treatment for patients with both primary T-cell and B-cell cutaneous NHL. Forty-one patients, 25 with primary cutaneous T-cell NHL (CTCL) (16 MF, 4 SS, 5 PTCL) and 16 with CBCL (4 MZL, 3 FCL, 8 DLBL, 1 lymphoblastic NHL) were included in this study. Of the 25 CTCL patients, 20 were males (median age 48y); 16 received IFN-a as first line treatment, 5 after PUVA and 4 after failure of other treatment modalities. Of the 16 CBCL patients, 8 were males (median age 57y); 14 received IFN-a frontline and 2 after treatment failure. Three to 5 MU IFN-a were administered subcutaneously daily with paracetamol prophylactically 1 hour before injection and two hours after. 17 out of 24 CTCL patients responded (overall response rate 71%, 42% CR and 29% PR) (12/16 MF, 1/4 SS and 3/5 PTCL). Median time to response was 4 months (1–17). Median duration of response was 15 months (8–38). 11 patients relapsed, 1 responder rapidly discontinued treatment because of side effects (cataract), the others are still under treatment with IFN-a. Among patients with CBCL 12/14 responded (overall response rate 86%, 64% CR and 22% PR). Median time to response was 2 months (1–4) and median response duration 23 months (13–30); 4 patients relapsed, 1 discontinued treatment because of side effects (depression), another continued with Peg- IFN because of chronic fatigue and the others are still under IFN-a treatment. With respect to histologic subtype, all 4 MZL patients responded; 2/3 FCL and 4/8 DLBL also responded. Flu-like syndrome was observed in the majority of patients at treatment initiation and 60% of patients presented mild leukopenia. In conclusion IFN-a is an effective treatment in primary cutaneous NHL and is usually well tolerated. As already reported response rate is satisfactory in MF. The high response rate observed in CBCL, especially in low-grade subtypes, but also in half of DLBL patients has not been reported previously.

A Phase II Study of Denileukin Diftitox (Ontak®) with CHOP Chemotherapy in Patients with Newly-Diagnosed Aggressive T-Cell Lymphomas, the CONCEPT Trial: Interim Analysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2461-2461 ◽  
Author(s):  
Francine M. Foss ◽  
Nelida Sjak-Shie ◽  
Andre Goy ◽  
Ranjana Advani ◽  
Eric Jacobsen ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Newly Diagnosed ◽  
Chop Chemotherapy ◽  
Overall Response ◽  
Denileukin Diftitox ◽  
T Cell Lymphomas

Abstract Denileukin diftitox, a genetically engineered fusion protein comprised of the enzymatically active domain of diphtheria toxin and the full length sequence of human interleukin-2 (IL-2) that targets malignancies expressing the IL-2 receptor, is approved for cutaneous T-cell lymphoma and has demonstrated a 48% objective response rate in relapsed/refractory PTCL. Because denileukin diftitox is not myelosuppressive and induces apoptosis by inhibition of protein synthesis, a mechanism of action non-cross-resistant with chemotherapy, we evaluated the efficacy and safety of the combination of denileukin diftitox plus CHOP in newly diagnosed aggressive T-cell lymphomas. In this multicenter Phase II study, patients (pts) with aggressive T-cell histologies according to REAL classification were eligible. Pts were required to have absolute neutrophil count ≥1000, platelets ≥50,000, adequate renal and hepatic function with serum albumin ≥3.0 g/dL, and LVEF ≥50%. Denileukin diftitox was given by IV infusion at 18 mcg/kg/day on Days 1 and 2 of each cycle, followed by CHOP chemotherapy on Day 3, and G-CSF support starting Day 4 of each cycle. Cycles were administered every 3 weeks for up to 6 cycles. Restaging evaluation of response is performed after every 2 cycles. The study objective for efficacy is to achieve an overall response rate (CR+PR) of 70%. Twenty-one patients (76% PTCLnos) have been enrolled to date, with a median age of 56 (range 40–80), 10 male, and 11 female. Six patients are not evaluable for response; one discontinued therapy during Cycle 1 due to a hypersensitivity reaction, and 5 are too early to evaluate (1 cycle of therapy given). For the 15 evaluable patients, the overall response rate is 87% with 9 CR or CRu (60%), 4 PR (27%) and 1 each for stable and progressive disease (see Table below). Four of 13 responders (31%) have progressed, with duration of response ranging from 1.5 to 5.9 months. Toxicities have generally been grade 1–2, were transient, and caused few treatment delays. The most common adverse events have been edema (27%), elevated transaminases (20%), and hypoalbuminemia (14%). Only two Grade 4 toxicities were noted (one each of neutropenia and deniluekin diftitox infusion-related allergic reaction). This is the first trial to report on the use of ONTAK in combination with chemotherapy. The novel combination of denileukin diftitox and CHOP appears to be clinically active, and is well tolerated with no unexpected, new, or overlapping toxicities. Pt accrual is ongoing. PTCL subtype No. of Patients No. evaluable Responses ORR PTCLnos 16 12 4 CR 4 CRu, 3 PR, 1 PD 92% Angioimmunoblastic 2 1 1 PR 50% Enteric T-cell 2 2 1 CR, 1 SD 50% Subcutaneous panniculitic 1 0 n/a n/a

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