Dose-escalation study of CHOP with or without prophylactic G-CSF in aggressive non-Hodgkin's lymphoma

Background:CHOP is accepted as the gold standard for first linechemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalationstudy of CHOP was conducted to determine the maximal tolerated dose (MTD) andtoxicity profile of CHOP at three-week intervals with or without prophylacticrecombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patientswith aggressive NHL. Patients and methods:The doses of drugs were escalated from 50mg/m² to 70 mg/m² for doxorubicin and from 750mg/m² to 2250 mg/m² for cyclophosphamide, withconventional doses of vincristine and oral prednisolone. After the MTD wasdetermined without rHuG-CSF, dose escalation was conducted with prophylacticrHuG-CSF. Results:Thirty-three patients with NHL were enrolled into thestudy. The MTD without prophylactic rHuG-CSF was 70 mg/m² ofdoxorubicin and 1250 mg/m² of cyclophosphamide, with neutropeniaas a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70mg/m² of doxorubicin and 2250 mg/m² of cyclophosphamide.The overall response rate was 100% (76% complete response and24% partial response). Progression-free survival and overall survivalat five years were 45% and 66%, respectively. Conclusions:Significant dose escalation of doxorubicin andcyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy ofdose-escalated CHOP should be compared with that of standard CHOP.     

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.     

A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL

Background:Standard therapy for lymphoma consists of acyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP)combination regimen. Liposomal daunorubicin (DaunoXome®) is an alternativeto doxorubicin for patients with lymphoma because of its more favorable safetyprofile and potentially more selective uptake in lymphoma. The objectives ofthis study were to determine the maximum tolerated dose (MTD) of liposomaldaunorubucin with CVP (COP-X) and the tolerability of the regimen in patientswith indolent lymphoma. Patients and methods:Patients with low-grade andintermediate-grade lymphoma having adequate cardiac, hepatic, and renalfunction were enrolled. Patients received C 750 mg/m², V 1.4mg/m² (maximum 2.0 mg), and liposomal daunorubicin 50–100mg/m² i.v. on day 1 and P 100 mg p.o. on days 1–5. MTD wasthe liposomal daunorubicin dose associated with 20% dose-limitingtoxicity (ANC <500/mm³ for >5 days or febrile neutropenia). Results:Twenty patients, median age 59 years, were treated. Theliposomal daunorubicin MTD combined with CVP was 70–80 mg/m²,depending on patient population. No significant non-hematologic toxicityoccurred. Response rate was 44% (2 complete and 5 partial responses). Conclusions:A liposomal daunorubicin dose of 80 mg/m²in the COP-X regimen was well tolerated with little non-hematologic toxicity.     

Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: A multicentre,single-arm,phase 2 trial

BackgroundWe performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results.MethodsPatients received bortezomib on days 1 and 8 at a dose of 1.6 mg/m² in addition to CHOP every 3 weeks for a total of six cycles.ResultsForty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n = 16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n = 10), angioimmunoblastic T-cell lymphoma (AITL, n = 8), ALK-negative anaplastic large-cell lymphoma (ALCL, n = 6), cutaneous T-cell lymphoma (CTCL, n = 5) and hepatosplenic T-cell lymphoma (n = 1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy.ConclusionsThe combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission.     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

Dose-escalation of CHOP in non-Hodgkin's lymphoma

Background: CHOP is considered to be the gold standard for patients with histologically aggressive non-Hodgkin's lymphoma both in limited and advanced stages. In order to determine the maximum tolerable dose of an intensified CHOP regimen, a dose-escalation study of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with non-Hodgkin's lymphoma (NHL) was started.Patients and methods: With an increased fixed dose of doxorubicin at 75 mg/m2 instead of 50 mg/m2 on day 1 and standard doses of vincristine (1.4 mg/m2 on day 1) and prednisone (100 mg day 1 through 5), cyclophosphamide dose was escalated by increments of 250 mg/m2 in consecutive cohorts of at least three patients starting from 1000 mg/m2. Granulocyte-colony stimulating factor (G-CSF) support was added to the regimen starting from the dose-level inducing grade 4 neutropenia lasting more than five days in two patients. Dose limiting toxicity was defined as either the dose inducing grade 4 neutropenia lasting more than seven days despite the use of G-CSF, or grade 3–4 thrombocytopenia lasting more than seven days, or any grade 4 non-hematological toxicity other than alopecia. The dose-level below the one inducing dose-limiting toxicity was defined as maximum tolerable dose. All patients were treated on an outpatient basis. Dose-intensity parameters for single agent doxorubicin and cyclophosphamide as well as for the whole regimen were evaluated.Results: Eighty-seven patients are evaluable over a four-year study period. At 1750 mg/m2 dose-level, G-CSF was added to the regimen according to described criteria. At the cyclophosphamide dose of 3000 mg/m2, dose-limiting hematological toxicity occurred in two patients, with one grade 4 thrombocytopenia and neutropenia and one grade 4 neutropenia lasting more than seven days. Thus, cyclophosphamide dose of 2750 mg/m2 was defined as maximum tolerable dose.Conclusions: CHOP intensification of approximately 1.8 times that of the standard regimen is feasible and safely administered on an outpatient basis with G-CSF support. Further investigation on the role of dose-intensity in the outcome of NHL should focus on the comparison of intensified CHOP regimen and standard CHOP or high-dose chemotherapy.     

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer

Purpose  This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. Patients and methods  Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m² of bortezomib with 15 mg/m² of doxorubicin to 1.5 mg/m² of bortezomib with 20 mg/m² of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. Results  The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m² bortezomib, 20 mg/m² doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m² bortezomib, 15 mg/m² doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. Conclusions  Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m² intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease. Supported by grant: U01 CA062491 “Early Clinical Trials of Anti-Cancer Agents With Phase I Emphasis, NCI” and M01 RR03186 “General Clinical Research Center Program of The National Center for Research Resources, NIH”.     

Randomized phase II study of biweekly CHOP and dose-escalated CHOP with prophylactic use of lenograstim (glycosylated G-CSF) in aggressive non-Hodgkin's lymphoma: Japan Clinical Oncology Group Study 9505.

BACKGROUND: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for first-line chemotherapy in aggressive non-Hodgkin's lymphoma (NHL). However, the therapeutic efficacy of CHOP remains unsatisfactory, particularly in high-intermediate risk and high risk patients, and a new strategy is warranted in this patient population. The aim of the present study was to explore a suitable therapeutic-intensified regimen for the treatment of aggressive NHL. PATIENTS AND METHODS: Between May 1995 and July 1998, a total of 70 patients with high-intermediate risk or high risk aggressive NHL, according to the International Prognostic Index, were enrolled and randomly assigned to receive either eight cycles of standard CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2) and prednisolone 100 mg for 5 days) every 2 weeks, or six cycles of dose-escalated CHOP (cyclophosphamide 1500 mg/m(2), doxorubicin 70 mg/m(2), vincristine 1.4 mg/m(2) and prednisolone 100 mg for 5 days) every 3 weeks. Lenograstim (glycosylated rHuG-CSF), at a dose of 2 micro g/kg/day s.c., was administered daily from day 3 until day 13 with biweekly CHOP and until day 20 with the dose-escalated CHOP. The primary endpoint was complete response rate. RESULTS: The complete response rate was 60% [21 of 35; 95% confidence interval (CI) 42% to 76%] with biweekly CHOP and 51% (18 of 35; 95% CI 34% to 69%) with dose-escalated CHOP. The major toxicity was grade 4 neutropenia and was more frequent in the dose-escalated CHOP arm (86%) than in the biweekly CHOP arm (50%). Grade 4 thrombocytopenia was also more frequent in the dose-escalated CHOP arm (20%) than the biweekly CHOP arm (3%). Non-hematological toxicities were acceptable in both arms. One treatment-related death (due to cardiac arrhythmia) was observed in a dose-escalated CHOP patient. Progression-free survival at 3 years was 43% (95% CI 27% to 59%) in the biweekly CHOP arm and 31% (95% CI 16% to 47%) in the dose-escalated CHOP arm. Although seven patients were deemed ineligible by central review of the pathological diagnosis, the results for both eligible and all enrolled patients were similar. CONCLUSIONS: Similar complete response rates and progression-free survival rates, but lower toxicity, indicated that biweekly CHOP was superior to dose-escalated CHOP in the treatment of aggressive NHL. Based on these results, the Lymphoma Study Group of the Japan Clinical Oncology Group is conducting a randomized phase III study comparing biweekly CHOP with standard CHOP in newly diagnosed patients with advanced-stage aggressive NHL.     

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.     

A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

BackgroundStandard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.Patients and MethodsPatients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m²/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.ResultsNine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m² dose level. There was no clear evidence of suppression of nuclear factor-κB target gene expression in biopsy samples.ConclusionThe MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.     

Complete remission in two cases of adult T-cell leukemia/lymphoma treated with hyper-CVAD: a case report and review of the literature

BackgroundAcute T-cell leukemia/lymphoma (ATLL) is a post thymic (peripheral) T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). Historically, the chemotherapy regimen CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) has been the standard treatment of this rare malignancy. However, its prognosis is poor and median survival in the aggressive variants of ATLL is only 6-10 months. Recently, a more aggressive regimen piloted in Japan, vincristine/cyclophosphamide/doxorubicin/prednisone (VCAP)- doxorubicin/ranimustine/prednisone (AMP)- vindesine/etoposide/carboplatin/prednisone (VECP), has been reported to yield better survival results over biweekly CHOP in a phase III trial. However, the hyper- cyclophosphamide/vincristine/doxorubicin/dexamethasone (CVAD) regimen is a much more frequently used regimen for the treatment of aggressive hematologic malignancies, and has a higher intensity then CHOP. Yet, there is little reported experience with hyper-CVAD regimen in ATLL.Case ReportsWe present 2 patients diagnosed with ATLL who were treated with hyper-CVAD chemotherapy and have achieved a durable complete remission. One of the patients has gone on to receive an allogeneic bone marrow transplantation and has been in complete remission for over 18 months. The other has been in a continuous remission for approximately 12 months. We also review the past published experience with the hyper-CVAD regimen in patients with ATLL.ConclusionA commonly used chemotherapy regimen for aggressive hematologic malignancies, hyper-CVAD, can induce durable remissions in patients with ATLL.     

Long-term outcome of mesna,ifosfamide, mitoxantrone,etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP

In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m², ifosfamide 1.3 g/m², etoposide 65 mg/m² on days 1–3, and mitoxantrone 12 mg/m² on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30–73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9–195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five- and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients.     

A phase-I study evaluating the combination of pegylated liposomal doxorubicin and paclitaxel as salvage chemotherapy in metastatic breast cancer previously treated with anthracycline

Purpose The two main goals of this phase-I study were to determine the maximum-tolerated dose (MTD) and to characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Lipo-Dox) and paclitaxel (PTX) administered on a 3-week schedule in patients with metastatic breast cancer (MBC) who had previously been treated with anthracycline-based therapy. Methods This phase-I study was performed via a two-staged dose escalation schema. The initial doses were PLD 30 mg/m² and PTX 150 mg/m², administered intravenously once every 21 days. The dose of PLD was escalated in increments of 5 mg/m² until the MTD was reached, at which time the PTX was then increased in increments of 10 mg/m² until the MTD was reached. Results Twenty-three patients received between 1 and 13 treatment cycles. In stage I of the study, 14 patients received a fixed dose of PTX 150 mg/m² while PLD escalated from 30 mg/m². At 40 mg/m², PLD resulted in dose-limiting toxicities (DLT) including febrile neutropenia and palmar-plantar erythrodysesthesia that occurred in two of five patients. In stage II of the study, nine patients received fixed dose of PLD 35 mg/m² and escalating doses of PTX starting at 160 mg/m². At PTX 170 mg/m² and dose-limiting neutropenic fever occurred in two of five patients. Out of 19 evaluable patients, 10 (52.6%) achieved objective response (one complete response and nine partial response), and 5 had stable disease. Conclusions The maximal tolerated doses of PLD and PTX are 35 and 160 mg/m², respectively, administered every 3 weeks. The combination of PLD (30–35 mg/m²) and PTX (150–160 mg/m²) constitutes an active regimen with mild toxicity that merits further study.     

Efficacy and Safety of the Modified EPOCH Regimen (Etoposide,Vincristine, Doxorubicin,Carboplatin, and Prednisolone) for Adult T-cell Leukemia/Lymphoma: A Multicenter Retrospective Study

BackgroundWe retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen.Patients and MethodsPatients received up to 6 mEPOCH cycles. Etoposide (50 mg/m²/day), doxorubicin (10 mg/m²/day), and vincristine (0.4 mg/m²/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m²/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert’s formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6.ResultsIn 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation.ConclusionThe mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.     

Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF mobilized peripheral blood progenitor cell support in patients with metastatic breast cancer

Background: In a previous study we applied doxorubicin and cyclophosphamide in a dose-intensive regimen with GM-CSF to patients with metastatic breast cancer (MBC). That treatment failed to prolong the remission duration compared to conventional-dose chemotherapy. In the present study we escalated the dosages of the same agents to: 1) determine the maximum tolerated dosages (MTD) when given for three cycles with G-CSF mobilised peripheral blood progenitor cell (PBPC) reinfusion and 2) evaluate the antitumour effect of this regimen.Patients and methods: For mobilisation of PBPC, G-CSF 15 µg/kg/day was given subcutaneously (s.c.), and in subsequent cohorts leucapheresis was started on days 3, 4 or 6. The intention was to treat MBC patients with three cycles of doxorubicin and cyclophosphamide at a starting dose of doxorubicin 90 mg/m² and cyclophosphamide 1000 mg/m². Dosages were then escalated in subsequent cohorts of at least three patients. In case of dose-limiting mucositis, only the dose of cyclophosphamide was escalated in the next cohort.Results: Twenty-one patients entered this protocol, of which 18 patients received high-dose chemotherapy. The mobilisation of PBPC using G-CSF only was sufficient for three cycles of high-dose chemotherapy in 10 of 21 (47%) patients. Mucositis precluded dose escalation of doxorubicin beyond 110 mg/m². The MTD in this combination was 110 mg/m² for doxorubicin, and 4 g/m² for cyclophosphamide, with haemorrhagic cystitis being the dose-limiting toxicity. The overall response rate was 78% (95% confidence interval (95% CI): 57%–97%), with 22% (95% CI: 3%–41%) complete responses.Conclusion: The MTD of this three cycle high-dose regimen was doxorubicin 110 mg/m² and cyclophosphamide 4 g/m² with mucositis and cystitis being dose-limiting toxicities. Although the primary aim was not the evaluation of antitumour effect, this high-dose regimen does not appear to provide an improvement of treatment results in comparison with our previous study with the same drugs at moderately high-dosages without stem cell support.     

High dose intensity doxorubicin in aggressive non-Hodgkin's lymphoma: a literature-based meta-analysis

Background: Aggressive non-Hodgkin's lymphoma (NHL) represents ∼60% of lymphomas in the West and even more in the developing world. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recognized as the standard chemotherapy regimen and the addition of rituximab to B-cell subtypes has been shown to significantly improve treatment outcomes. Nevertheless, still a significant fraction of patients is not offered rituximab due to economic reasons. Thus, CHOP is still offered to these patients as well as those with T-cell subtypes. Data from the early 1990s have indicated that the dose intensity (DI) of doxorubicin is a key factor in predicting survival.Methods: A Medline and Cochrane library search was carried out using the search terms ‘CHOP’, ‘lymphoma’ and ‘randomized trials’. Eligible trials had CHOP as a control arm and any regimen administering doxorubicin at a higher DI (16.6 mg/m²/week) as the investigational arm. Pooling of data was carried out using the mixed effect model.Results: Eight trials were eligible. Patients receiving DI doxorubicin-based regimens had a significantly better overall survival [summary hazard ratio (SHR) 0.82; 95% confidence interval (CI) 0.71–0.96], event-free survival (SHR 0.86; 95% CI 0.75–0.99) and higher complete response rate (summary odds ratio 0.91; 95% CI 0.67–0.97).Conclusion: High DI doxorubicin based should be considered in patients with aggressive NHL.     

Dose density and dose intensity: where does CHOP go from here?

Non-myeloablative chemotherapy regimens have not been fullyexplored in the treatment of aggressive non-Hodgkin’slymphomas [1]. Two important concepts in the development ofnew chemotherapy regimens are dose intensity [dose of effectivedrug administered per unit time (mg/m²/week), calculated perweek even when the agent is administered once every 3 weeksas in CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)]and dose density (the frequency of effective drug dose administered)[2, 3]. In aggressive non-Hodgkin’s lymphomas, myeloablativedose intensity has been successfully established in the autologousstem     

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m², the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m²/day on days 1–4, vincristine 0.4 mg/m²/day on days 1–4, doxorubicin 10 mg/m²/day on days 1–4, cyclophosphamide 750 mg/m²/day on day 6, and prednisolone 60 mg/m²/day on days 1–6). Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.Key Words: Bortezomib, Multiple myeloma, Peripheral neuropathy, Dorsal column degeneration     

Intensified alemtuzumab–CHOP therapy for peripheral T-cell lymphoma

BackgroundThe prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab–chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON).Patients and methodsPatients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight.ResultsTwenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19–41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment.ConclusionsAlthough intensified alemtuzumab–CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.