Salvage chemoimmunotherapy with rituximab,ifosfamide and etoposide (R‐IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high‐dose methotrexate‐based chemotherapy

Despite a high proportion of patients with primary CNS lymphoma (PCNSL) experiences failure after/during first‐line treatment, a few studies focused on salvage therapy are available, often with disappointing results. Herein, we report feasibility and activity of a combination of rituximab, ifosfamide and etoposide (R‐IE regimen) in a multicentre series of patients with PCNSL relapsed or refractory to high‐dose methotrexate‐based chemotherapy. We considered consecutive HIV‐negative patients ≤75 years old with failed PCNSL treated with R‐IE regimen (rituximab 375 mg/m², day 0; ifosfamide 2 g/m²/day, days1–3; etoposide 250 mg/m², day 1; four courses). Twenty‐two patients (median age 60 years; range 39–72; male/female ratio: 1:4) received R‐IE as second‐line (n = 18) or third‐line (n = 4) treatment. Eleven patients had refractory PCNSL, and 11 had relapsing disease. Twelve patients had been previously irradiated. Sixty (68%) of the 88 planned courses were actually delivered; only one patient interrupted R‐IE because of toxicity. Grade 4 hematological toxicity was manageable; a single case of grade 4 non‐hematological toxicity (transient hepatotoxicity) was recorded. Response was complete in six patients and partial in three (overall response rate = 41%; 95%CI: 21–61%). Seven patients were successfully referred to autologous peripheral blood stem cell collection; four responders were consolidated with high‐dose chemotherapy supported by autologous stem cell transplant. At a median follow‐up of 24 months, eight responders did not experience relapse, two of them died of neurological impairment while in remission. Six patients are alive, with a 2‐year survival after relapse of 25 ± 9%. We concluded that R‐IE is a feasible and active combination for patients with relapsed/refractory PCNSL. This regimen allows stem cell collection and successful consolidation with high‐dose chemotherapy and autologous transplant. Copyright © 2012 John Wiley & Sons, Ltd.     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

Comparison of clinical remission and survival between CLAG and FLAG induction chemotherapy in patients with refractory or relapsed acute myeloid leukemia: a prospective cohort study

Purpose

To compare the clinical remission and survival between CLAG and FLAG induction chemotherapy in treating patients with refractory or relapsed acute myeloid leukemia (R/R AML).

Methods

103 R/R AML patients were consecutively enrolled in this prospective cohort study. 55 patients were treated by CLAG induction chemotherapy as follows: 5 mg/m²/day cladribine (days 1–5); 2 g/m²/day cytarabine (days 1–5) and 300 μg/day filgrastim (days 0–5). While 48 patients were treated by FLAG: 30 mg/m²/day fludarabine (days 1–5), 2 g/m²/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5).

Results

CLAG induction chemotherapy achieved 61.7% complete remission rate (CR) and 78.7% overall remission rate (ORR), which was similar with FLAG chemotherapy which realized 48.7% CR and 69.2% ORR. No difference of overall survival (OS) was discovered between two groups either. Age cytarabine 60 years, secondary disease, poor risk stratification and BM blast ≥ 42.7% and second or higher salvage therapy were independent factors for worse prognosis. Subgroups analysis revealed that in patients with second or higher salvage therapy, CLAG seemed to achieve a higher CR than FLAG. And in patients with relapsed disease, poor risk stratification or CR at first induction, CLAG seemed to realize a prolonged OS compared to FLAG.

Conclusion

CLAG was equally effective to FLAG induction chemotherapy in total R/R AML patients, while CLAG seemed to be a better option than FLAG in patients with relapsed disease, poor risk stratification, CR at first induction or second or higher salvage therapies.

     

Immune reconstitution of B‐cell lymphoma patients receiving CHOP‐based chemotherapy containing rituximab

Sixty‐six B‐cell lymphoma patients were treated with a CHOP‐based chemotherapy containing rituximab (R‐CHOP‐like regimen). Immune reconstitution was assessed by measuring lymphocyte subsets and immunoglobulins. Fifty‐five patients (83.3%) underwent six cycles of the R‐CHOP‐like regimen. CD19⁺ and CD20⁺ cells were completely eliminated from the peripheral blood after one cycle of the R‐CHOP‐like regimen; they were detected again 6 months after the therapy. One year after the therapy, B‐cell numbers recovered to their level at diagnosis and almost doubled 2 years after the therapy. The lowest numbers of CD3⁺, CD8⁺ and CD56⁺ cells were seen after three cycles of the regimen, but continued to increase until 1 year after the therapy, remaining stable thereafter. CD4⁺ T‐cells were at their lowest after six cycles of the regimen and recovered slowly for 2 years after the therapy; however, their numbers were still lower than that at diagnosis. Immunoglobulins decreased over six cycles of the R‐CHOP‐like regimen and then recovered gradually for 2 years after the therapy. The percentage of IgG, IgA and IgM 2 years after the therapy compared with those at diagnosis was 93.9%, 90.1%, 76.3%, respectively. Twelve infectious complications occurred which consisted of three febrile neutropenia, three Herpes Zoster, two tympanitis, two Pneumocystis jiroveci pneumonia and two hepatitis B virus reactivation. B‐cells required 1 year and CD4⁺ T‐cells and immunoglobulins needed 2 years to recover after the therapy. Copyright © 2010 John Wiley & Sons, Ltd.     

Multicentre phase II study of CyclOBEAP plus rituximab in patients with diffuse large B‐cell lymphoma

The R‐CHOP regimen has been found to improve the outcome of diffuse large B‐cell lymphoma (DLBCL). However, it does not provide a satisfactory treatment outcome in the high‐risk group. We previously administered the CyclOBEAP regimen to patients with DLBCL, and reported its safety and efficacy. The R‐CyclOBEAP regimen was administered over a total period of 12 weeks, and rituximab 375 mg/m² was given every 2 weeks. There were 101 eligible patients. CR was achieved in 96 patients (95%). The 5‐year overall survival (OS) rate was 85% and progression‐free survival (PFS) rate was 76%. When the patients were divided according to the IPI, the 5‐year OS and PFS rates did not significantly differ among the risk groups. The 5‐year PFS of the germinal centre B‐cell group was 80% and that of the non‐GCB group was 74% (NS). Univariate analysis showed that the presence of B symptoms, extranodal lesions ≧2, and sIL‐2R were significant poor prognostic factors. Grade 4 neutropenia was observed in 91 patients and thrombocytopenia in 9 patients. The addition of rituximab to CyclOBEAP therapy may enhance the effect of CyclOBEAP therapy for DLBCL. Copyright © 2010 John Wiley & Sons, Ltd.     

Response and survival benefit with chemoimmunotherapy in Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV‐positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV‐positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R‐CHOP] and 16 with CHOP), and 84 were EBV‐negative (all treated with R‐CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV‐positive DLBCL patients (R‐CHOP versus CHOP) and in DLBCL patients treated with R‐CHOP (EBV‐positive vs EBV‐negative). There were no differences in the clinical characteristics between EBV‐positive and EBV‐negative DLBCL patients. Among EBV‐positive DLBCL patients, R‐CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75‐13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09‐0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18‐1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32‐2.67; P = .89) between EBV‐positive and EBV‐negative DLBCL patients treated with R‐CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV‐positive DLBCL patients. Epstein‐Barr virus status does not seem to affect response or survival in DLBCL patients treated with R‐CHOP.     

Efficacy and safety of the combination of rituximab,fludarabine, and mitoxantrone for rituximab‐naive,recurrent/refractory follicular non‐Hodgkin lymphoma with high tumor burden

BACKGROUND:

This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R‐FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

METHODS:

Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP‐like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion >7cm), 56% had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3‐5), and 22% were refractory. Treatment consisted of 4 courses of R‐FM (rituximab 375 mg/m² intravenously on Day 1, fludarabine 25 mg/m² intravenously on Days 2 through 4, and mitoxantrone 10 mg/m² intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab).

RESULTS:

The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R‐FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow‐up of 4 years, the 3‐year progression‐free survival rate was 47%, the event‐free survival rate was 41%, and the 3‐year overall survival rate was 66%. Grade ≥3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively.

CONCLUSIONS:

Cytoreduction with 4 courses of R‐FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome. Cancer 2010. © 2010 American Cancer Society.     

Receptor tyrosine kinases MET and RON as prognostic factors in diffuse large B‐cell lymphoma patients receiving R‐CHOP

Receptor tyrosine kinases MET and RON (MST1R) form non‐covalent complexes on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role for MET expression in diffuse large B‐cell lymphoma (DLBCL). The aim of this study was to examine the impact of MET and RON expression in uniformly treated DLBCL patients. The expression of MET and RON was retrospectively examined by immunohistochemistry in 120 DLBCL patients treated with rituximab combined with a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). The median follow‐up time was 42.5 months (range, 1–89 months). Thirty‐two (26%) and 30 patients (25%) expressed MET or RON, respectively. Seventy‐five patients (62.5%) were negative for both MET and RON (MET ^? RON ^? ). MET negativity was associated with worse overall survival (P = 0.029). In multivariate analysis, negativity for both MET and RON (MET ^? RON ^? ) was strongly associated with inferior overall survival (P = 0.008). Interestingly, the MET^?RON^? phenotype retained its prognostic impact after subgroup analysis according to the international prognostic index or by the cell of origin by immunohistochemical algorithm by Choi et al. This study suggests that the MET ^? RON^? phenotype is an independent prognostic factor in DLBCL patients receiving R‐CHOP, and may identify a subgroup of DLBCL patients who require more intensive therapy.     

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

BACKGROUND:

The outcome of patients with systemic diffuse large B‐cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high‐risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high‐dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R‐CHOP) chemotherapy to decrease CNS recurrence in high‐risk patients.

METHODS:

A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression‐free survival, and overall survival were calculated.

RESULTS:

Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m² with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow‐up of 33 months, there were only 2 CNS recurrences (3%) in this high‐risk population. The 3‐year progression‐free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients.

CONCLUSIONS:

Intravenous methotrexate can be safely administered concurrently with R‐CHOP and is associated with a low risk of CNS recurrence in high‐risk patients. Cancer 2010. © 2010 American Cancer Society.     

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non‐t(15;17) subtype

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated. Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French – American – British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m²/day p.o., mercaptopurine 60 mg/m²/day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m²/d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients). Results: In all patients the rates of CR, 3‐year OS and 5‐year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5‐year OS and 5‐year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively. Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.     

Early versus late intensification for patients with high‐risk Hodgkin lymphoma—3 Cycles of intensive chemotherapy plus low‐dose lymph node radiation therapy versus 4 cycles of combined doxorubicin,bleomycin, vinblastine,and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation

BACKGROUND.

The 5‐year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post‐treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high‐risk factors who were recruited between May 1997 and December 2004.

METHODS.

High‐risk CS IIB, III, and IV were defined by the presence of ≥5 involved lymphoid areas, and/or a mediastinal mass ratio ≥0.45, and/or ≥2 extra lymph node sites affected by the disease (for CS IV). In Arm V, 82 patients received 3 courses of combined vindesine (5 mg/m²), doxorubicin (99 mg/m²), carmustine (140 mg/m²), etoposide (600 mg/m²), and methylprednisolone (600 mg/m²) (VABEM) followed by low‐dose lymph node irradiation. In Arm A, 76 patients received 4 cycles of ABVD followed by myeloablative combined carmustine (300 mg/m²), etoposide (800 mg/m²), cytarabine (1600 mg/m²), and melphalan (140 mg/m²) and underwent autologous stem cell transplantation.

RESULTS.

After 3 cycles of VABEM, the CR rate was 89% versus 60% after 4 cycles of ABVD. However, after the completion of treatment, the CR rates for Arms V and A were similar (89% and 88%, respectively). The 5‐year FFTF rates for Arms V and A also were similar (79% and 75%, respectively) along with the 5‐year overall survival rates (87% and 86%, respectively).

CONCLUSIONS.

Early intensification (Arm V) and late intensification (Arm A) were equally effective for treating patients with high‐risk/advanced HL. Cancer 2008. © 2008 American Cancer Society.     

Intensive chemotherapy improves survival in pediatric high‐grade glioma after gross total resection: results of the HIT‐GBM‐C protocol

BACKGROUND:

The authors hypothesized that intensified chemotherapy in protocol HIT‐GBM‐C would increase survival of pediatric patients with high‐grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG).

METHODS:

Pediatric patients with newly diagnosed HGG and DIPG were treated with standard fractionated radiation and simultaneous chemotherapy (cisplatin 20 mg/m² × 5 days, etoposide 100 mg/m² × 3 days, and vincristine, and 1 cycle of cisplatin + etoposide + ifosfamide 1.5 g/m × 5 days [PEI] during the last week of radiation). Subsequent maintenance chemotherapy included further cycles of PEI in Weeks 10, 14, 18, 22, 26, and 30, followed by oral valproic acid.

RESULTS:

Ninety‐seven (pons, 37; nonpons, 60) patients (median age, 10 years; grade IV histology, 35) were treated. Resection was complete in 21 patients, partial in 29, biopsy only in 26, and not performed in 21. Overall survival rates were 91% (standard error of the mean [SE] ± 3%), 56%, and 19% at 6, 12, and 60 months after diagnosis, respectively. When compared with previous protocols, there was no significant benefit for patients with residual tumor, but the 5‐year overall survival rate for patients with complete resection treated on HIT‐GBM‐C was 63% ± 12% SE, compared with 17% ± 10% SE for the historical control group (P = .003, log‐rank test).

CONCLUSIONS:

HIT‐GBM‐C chemotherapy after complete tumor resection was superior to previous protocols. Cancer 2010. © 2009 American Cancer Society.     

Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255

Background:Patients with resistant diffuse aggressivenon-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggestedinfusional therapy may be beneficial. Patients and methods:This trial used an infusional regimen calledI-CHOPE in resistant patients who had previously received only bolus CHOPE orCHOP regimen. Resistance was defined as: a) primary refractory disease, b)progression on therapy, c) partial response, d) complete remission lastingless than one year. Eligibility criteria included a diagnosis of DA-NHL (IWFE-H), no prior irradiation and adequate organ function. Results:Thirty-seven patients were entered and twenty-nine wereeligible. Reasons for ineligibility were incorrect histology (5) and other(3). The median age was 57 years (range 29–81) with 21 males. Theperformance status scores were: 0 (12 patients); 1 (9 patients); 2 (8patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE(2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hourcontinuous intravenous infusion of doxorubicin 10 mg/m²/day,vincristine 0.28 mg/m²/day (maximum 0.4 mg/day), and etoposide 48mg/m²/day. Cyclophosphamide 750 mg/m² was given as aniv bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1–5.G-CSF was allowed for myelosuppression. The overall response rate was48% (CR 17%; PR 31%). Freedom from progression was24% at six months and 8% at one year. Survival was 69%at six months and 40% at one year. In an exploratory analysis a priorCR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had aCR/PR on previous therapy responded while two of thirteen who had no priorresponse, responded to I-CHOPE (P= 0.003). The toxicity wastolerable with grade 3–4 hematologic toxicity being leucopenia94% and thrombocytopenia 41%. The grade 3–4non-hematologic toxicities were infection in 28%, phlebitis in11%, and stomatitis in 15%. Conclusions:I-CHOPE can induce responses in this group ofpatients with a poor prognosis, but most were seen in those who had previouslyhad a response to bolus chemotherapy.     

Efficacy and toxicity of 2 schedules of frontline rituximab plus cyclophosphamide,doxorubicin, vincristine,and prednisone plus bortezomib in patients with B‐cell lymphoma

BACKGROUND:

Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with the addition of bortezomib in patients with B‐cell lymphoma.

METHODS:

Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R‐CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m² in Arm A and 1.3 mg/m² in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m² and 1.6 mg/m² in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.

RESULTS:

Forty‐nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.

CONCLUSIONS:

R‐CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose‐limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies. Cancer 2009. © 2009 American Cancer Society.     

ABCG2 Q141K polymorphism is associated with chemotherapy‐induced diarrhea in patients with diffuse large B‐cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/ vincristine/prednisone chemotherapy

ATP‐binding cassette transporter G2 (ABCG2) is the most recently described transporter of the multidrug‐resistance pump and it promotes resistance to anticancer drugs such as doxorubicin, mitoxantrone, topotecan, and SN‐38. Of the ABCG2 polymorphisms, V12M and Q141K alter the functional activity of the ABCG2 transporter and influence the drug response and various toxicities to chemotherapeutic agents. We therefore evaluated the impact of the ABCG2 V12M and Q141K polymorphisms on the therapeutic outcomes and toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R‐CHOP) therapy in 145 Korean patients with diffuse large B‐cell lymphoma (DLBCL). ABCG2 V12M and Q141K genotyping was carried out by pyrosequencing of polymerase chain reaction products. The clinical characteristics, treatment outcomes, toxicities of the patients, and the predictive value of the polymorphisms on response, survival, and adverse events to R‐CHOP for 145 patients were analyzed according to the ABCG2 V12M and Q141K polymorphisms. No differences were observed according to ABCG2 Q141K and V12M genotype in patient characteristics, disease characteristics, response, survival, or hematology toxicity profiles in patients with DLBCL who received frontline R‐CHOP chemotherapy. On multivariate analysis, grade I–IV diarrhea was statistically significant according to ABCG2 Q141K polymorphism (the QQ genotype vs the QK or KK genotypes; hazard ratio 2.835; 95% confidence interval 1.432–5.613; P = 0.003). This study demonstrates that the ABCG2 Q141K polymorphism may correlate with chemotherapy‐induced diarrhea in patients with DLBCL who have received frontline R‐CHOP chemotherapy, and this has implications for optimizing treatment with such agents. (Cancer Sci 2008; 99: 2496–2501)     

Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced,aggressive T-cell or NK/T-cell lymphoma

The aim of the study was to determine the maximum tolerated dose (MTD) and safety of the combination of bortezomib and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) as first-line therapy in advanced, aggressive T-cell lymphoma. Patients received increasing doses of bortezomib on days 1 and 8 (weekly schedule, 1.0, 1.3, and 1.6 mg/m²/dose) in addition to 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. Thirteen patients, who had stage III/IV chemonaive aggressive T-cell lymphoma, received a total of 55 cycles of treatment. One patient experienced hematologic dose-limiting toxicity (grade 4 neutropenia associated with febrile episode) at the 1.0 mg/m²/dose of bortezomib. There was no dose-limiting non-hematologic toxicity. The MTD was not reached at 1.6 mg/m² dose level of bortezomib. The overall complete remission rate in all patients was 61.5% (95% confidence interval = 31.6–86.1). Bortezomib can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced-stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II studies of bortezomib plus CHOP is 1.6 mg/m²/dose of bortezomib on days 1 and 8 every 3 weeks as first-line treatment.     

Immunophenotype and intermediate‐high international prognostic index score are prognostic factors for therapy in diffuse large B‐cell lymphoma patients

BACKGROUND.

The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B‐cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B‐cell (ABC), and not classified (NC) diffuse large B‐cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC‐DLBCL subtypes in identifying those high‐risk patients who may benefit from a more aggressive first‐line therapeutic approach.

METHODS.

From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC‐DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R‐CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC‐DLBCL patients received 6 R‐CHOP cycles and autologous stem cell transplantation.

RESULTS.

Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC‐DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4‐year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression‐free survival is 77% and 79% (P = .7), respectively.

CONCLUSIONS.

The autologous stem cell transplantation consolidation in the ABC&NC‐DLBCL subtypes induced the same rate of complete response (and similar progression‐free survival rate) compared with GCB‐DLBCL. In ABC&NC‐DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB‐DLBCL subset, without any significant difference in progression‐free survival rate. Cancer 2010. © 2010 American Cancer Society.     

Salvage chemotherapy with amrubicin and platinum for relapsed thymic carcinoma: experience in six cases

It has been reported that cisplatin-based chemotherapy shows beneficial effects in certain patients with advanced thymic carcinoma. However, the usefulness of salvage therapy has not been reported. We focused on a new anthracycline agent, amrubicin, combined with platinum compounds as salvage chemotherapy in patients with thymic carcinoma. Six cases of unresectable and locally advanced thymic carcinoma relapsed from prior cisplatin-containing chemotherapy were treated with amrubicin (30–40 mg/m² day 1–3) plus platinum compounds (cisplatin 60 mg/m² day 1 or nedaplatin 70 mg/m² day 1) chemotherapy as salvage chemotherapy. Two patients showed a partial response. However, Grade 3/4 neutropenia and thrombocytopenia occurred in all and two of the patients, respectively. We conclude that thymic carcinoma is sensitive to platinum-based chemotherapy and that amrubicin appears to have significant activity against thymic carcinoma. The major toxicity is hematological toxicities.     

Phase II feasibility study of preoperative chemotherapy with docetaxel,cisplatin, and fluorouracil for esophageal squamous cell carcinoma

The combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70–75 mg/m²) and cisplatin (70–75 mg/m²) on day 1, and continuous infusion of fluorouracil (750 mg/m²/day) on days 1–5. Antibiotic prophylaxis on days 5–15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty‐two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty‐one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment‐related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2‐year progression‐free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).     

A phase II study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma

Purpose

Adjuvant chemotherapy trial of TS-1 for gastric cancer study demonstrated that postoperative S-1 chemotherapy for 1 year improved overall survival of locally advanced gastric cancer (LAGC) patients. The goals of this study were to evaluate the feasibility and efficacy of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy.

Methods

In this single-center, open-label, phase II study, patients with potentially resectable adenocarcinoma of the stomach or gastroesophageal junction were eligible. For neoadjuvant chemotherapy, docetaxel 50 mg/m² on day (D) 1, oxaliplatin 100 mg/m² on D1, and S-1 40 mg/m² bid orally on D1–14 were administrated every 3 weeks for three cycles. After DOS chemotherapy, gastrectomy was performed, and then, adjuvant S-1 40 mg/m² bid was given on D1–28 every 6 weeks for 1 year. The primary endpoints were the proportion of patients who did not experience grade 3 or 4 toxicities (except grade 3 neutropenia) and R0 resection rates.

Results

A total of 41 patients were enrolled. All patients completed three planned cycles of neoadjuvant chemotherapy without disease progression. Eighteen patients (43.9 %) did not experience any grade 3–4 toxicity (except grade 3 neutropenia) during the neoadjuvant chemotherapy. All patients underwent surgery, and R0 resection was achieved in 40 patients (97.6 %).

Conclusion

Neoadjuvant DOS chemotherapy could be performed safely with a high R0 resection rate in LAGC patients. A phase III trial is currently underway.