Continuous Low-dose Cyclophosphamide Research Articles

Continuous low-dose cyclophosphamide plus prednisone in the treatment of relapsed and refractory multiple myeloma with severe complications.

We retrospectively analyzed the effective and safety of continuous low-dose cyclophosphamide combined with prednisone (CP) in relapsed and refractory multiple myeloma (RRMM) patients with severe complications. A total of 130 RRMM patients with severe complications were enrolled in this study, among which 41 patients were further given bortezomib, lenalidomide, thalidomide or ixazomib on the basis of CP regimen (CP+X group). The response to therapy, adverse events (AEs), overall survival (OS) and progression-free survival (PFS) were recorded. Among the 130 patients, 128 patients received therapeutic response assessment, with a complete remission rate (CRR) and objective response rate (ORR) of 4.7% and 58.6%, respectively. The median OS and PFS time were (38.0 ± 3.6) and (22.9±5.2) months, respectively. The most common AEs were hyperglycemia (7.7%), pneumonia (6.2%) and Cushing's syndrome (5.4%). In addition, we found the pro-BNP/BNP level was obviously decreased while the LVEF (left ventricular ejection fraction) was increased in RRMM patients following CP treatment as compared with those before treatment. Furthermore, CP+X regimen further improved the CRR compared with that before receiving the CP+X regimen (24.4% vs. 2.4%, P=0.007). Also, both the OS and PFS rates were significantly elevated in patients received CP+X regimen following CP regimen as compared with the patients received CP regimen only. This study demonstrates the metronomic chemotherapy regimen of CP is effective to RRMM patients with severe complications.

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

AbstractThe prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Efficacy of continuous low-dose cyclophosphamide and prednisone regimen in refractory multiple myeloma patients with severe heart failure

目的观察小剂量环磷酰胺联合泼尼松持续口服治疗复发/难治性多发性骨髓瘤（MM）伴严重心功能不全患者的临床疗效、安全性及心功能改善情况。方法选择75例MM伴心功能不全患者，给予环磷酰胺片（50 mg/d）联合泼尼松片（15 mg/d）进行小剂量化疗。结果75例患者中，失访2例，在可评估的73例患者中总有效率为64.4%，其中完全缓解（CR）2例（2.7%），很好的部分缓解（VGPR）4例（5.5%），部分缓解（PR）24例（32.9%）。中位生存时间为12（1~70）个月，中位治疗起效时间为90（16~120）d，中位无进展生存时间为12（1~60）个月。与治疗前比较，临床有效组患者血清B型脑钠肽下降[（906.4±104.8）ng/L对（336.6±30.3）ng/L，P<0.01]。患者常见的不良反应为骨髓抑制（32/73，43.8%）、感染（26/73，35.6%）和Cushing综合征（7/73，9.6%），一般可耐受或经对症处理后可缓解。结论小剂量环磷酰胺联合泼尼松持续口服治疗复发/难治性MM伴严重心功能不全患者可取得较好的疗效，并能改善患者心功能，具有良好的安全性。

Combined Treatment of Bortezomib, Continuous Low-Dose Cyclophosphamide and Dexamethasone Followed By One Year of Maintenance Treatment for Refractory or Relapsed Multiple Myeloma Patients: A Prospective Phase II Study

Introduction: Combination therapy for longer periods but at low dose, also called metronomic scheduling, might be an effective manner to treat patients with relapsing myeloma. In particular if the used agents attack the malignant clone in an alternative manner. Therefore we used the combination of bortezomib, dexametasone and daily low dose of oral cyclophosphamide as an induction regimen followed by one year of maintenance therapy consisting of bortezomib and cyclophosphamide.Methods: Relapsing myeloma patients, bortezomib naïve, were treated with three cycles of 1.3 mg/m2 bortezomib at day 1, 4, 8 and 11, cyclophosphamide 50 mg daily, and 20 mg dexamethasone at day 1, 2, 4, 5, 8, 9, 11 and 12 followed by three cycles of bortezomib 1.6 mg/m2 (day 1, 8, 15 and 2), cyclophosphamide (50 mg) daily and dexamethasone (20 mg) at day 1, 2, 8, 9, 15, 16, 22 and 23. Maintenance therapy consisting of bortezomib 1.3 mg/m2 every two weeks and daily dose of 50 mg cyclophosphamide for one year was applied to patients in partial or complete remission. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression free and overall survival.Results: 59 patients with relapsing multiple myeloma were included of whom 69% were in first relapse (Table 1). The upfront treatment consisted mainly of thalidomide-based and vincristine-based chemotherapy and 40% of the patients have been treated with an autologous stem cell transplantation. All 6 cycles of induction chemotherapy could be given in 49% of the patients. Premature discontinuation before starting maintenance therapy was due to toxicity (31%), progressive disease (7%), death (7%) or other reasons (6%). Myelosuppression was the most common side effect with WHO grade 3-4 in 31% of the patients. Neuropathy grade 3-4 was observed in 16% of patients, partially due to the fact that bortezomib was given intravenously during the first 2 yrs of the protocol which included 76% of the patients. Maintenance therapy was started in 47% of the patients with a median duration of 7.3 months (range 0.36.-13.4). Grade 3-4 toxicity was observed in 25% of the patients including infections (n=3) and myelosuppression (n=3) which did not resulted in discontinuation of therapy. Median follow up time was 29 months with an overall response of 62%, and a very good partial response (VGPR), complete remission (CR) in 21% and 7% of the patients respectively. During the maintenance phase an improvement in responsiveness was observed in 25% of the patients. The CR rate increased with 9% to a total of 16%. VGPR rate was 20% and 16% of the patient had a PR. At end of the maintenance therapy 50% of patients started with maintenance had stable disease. The median progression free survival (PFS) was 17.2 months (range 0.13 – 43.5) as depicted in figure 1. and the median overall survival was 21.6 months (range 0.46-54.4, figure 2). During follow up 33 % of the patients died due to progression of MM.Conclusion: The present study demonstrates that combination therapy with bortezomib, continuous low dose cyclophosphamide and dexamethasone is an effective and manageable regimen. Adding a year of maintenance was feasible with limited side effects and an increase in CR rate.Table 1:patient characteristicsPatients (%)Age, mean (min,max)69 (46-86)SexMale56Female44Relapse numberFirst relapse75Second relapse20Third relapse5Performance status06512925M-protein heavy chainIgA18IgG65Light chain disease18PolyneuropathyNo61Yes39 [Display omitted] [Display omitted] DisclosuresWaal de:Jansen Cilag: Research Funding. Munck de:Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. velden Van Der:Jansen Cilag: Research Funding. Tromp:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding. Vellenga:Jansen Cilag: Research Funding. Hovenga:Jansen Cilag: Research Funding.

Continuous low-dose cyclophosphamide and prednisone in the treatment of relapsed/refractory multiple myeloma with severe heart failure

Patients with relapsed/refractory (R/R) multiple myeloma (MM) complicated by severe heart failure typically do not tolerate conventional chemotherapy. Our previous study indicated that R/R MM patients with severe comorbidities could benefit from continuous low-dose oral cyclophosphamide and prednisone (CP regimen). We hereby performed a study of 56 R/R MM patients with severe heart failure (New York Heart Association class ≥ III) receiving the treatment of CP regimen. Among the 54 evaluable patients, clinical benefit was noted in 63.0% (complete response, 3.7%; very good partial response, 7.4%; partial response, 48.1%; stable disease, 3.7%). The median overall survival (OS) and progression-free survival (PFS) were 8 and 6 months. The left ventricular ejection fraction (LVEF) and the serum levels of B-type natriuretic peptide (BNP) were improved significantly. Slight adverse events were observed. In summary, the CP regimen is effective in R/R MM patients complicated with severe heart failure.

Peyronie's Disease Treated with Oral Weekly Dexamethasone and Continuous Low-dose Cyclophosphamide.

Peyronie's Disease Treated with Oral Weekly Dexamethasone and Continuous Low-dose Cyclophosphamide.

Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.

Erratum: Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

Erratum: Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors.

9500 Background: Angiogenesis is necessary for tumor growth, metastasis, and survival. Endothelial cells and pericytes, key cellular components of blood vessels, are primarily regulated by VEGF and PDGF signaling. We therefore performed a phase I trial to determine the feasibility and toxicity profile of agents combined to inhibit angiogenesis by targeting PDGFR-β and VEGFR2 with sorafenib, VEGF with bevacizumab, and endothelial cells with continuous low-dose CYC. Methods: Cohorts of 3-6 eligible patients with recurrent solid tumors received CYC and escalating dosages of sorafenib and then of bevacizumab (see table). Each course of therapy was 21 days. We used standard physical exams and laboratory tests to assess toxicities. Results: 19 patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1-23). The table summarizes dose levels explored and dose-limiting toxicities (DLTs) in course 1. With additional 71 courses of therapy, the most common nonhematologic toxicities ≥ grade 3 included rashes (5) and febrile neutropenia (2). Predominant hematologic toxicities were neutropenia and lymphopenia. Five of 17 evaluable patients had partial tumor responses (2 rhabdoid, 1 rhabdomyosarcoma, 1 medulloblastoma, 1 synovial sarcoma), and 9 had disease stabilization. First-dose pharmacokinetics results from 14 patients follow. The median (range) apparent CYC clearance was 2.03 L/hr/m2 (1.8-2.1 L/hr/m2), and the absorption rate constant was 0.12 hr-1 (0.08-0.23 hr-1). Sorafenib at 90 and 110 mg/m2yielded the following respective median (range) values: Cmax, 1.1 (0.37-2.4) and 1.6 (0.91-2.4) mg/L; Tmax, 8.5 (3.9-17.5) and 10.7 (8.2-14.1) h; AUC (0-12h), 10.4 (2.6-23.0) and 13.6 (8.0-20.4) mg*h/L. Conclusions: The recommended phase II doses are sorafenib, 90 mg/m2/dose BID; bevacizumab, 15 mg/kg q3 weeks; and CYC, 50 mg/m2 once daily. This regimen is feasible with promising evidence of anti-tumor activity that warrants further investigation. No. pts* Sorafenib (mg/m2) PO BID Bevacizumab (mg/kg) IV q3 wks No. DLT DLT course 1 3 90 5 0 None 4 110 5 2 Grd 3 rash, ↑lipase 6 90 10 1 Grd 3 thrombus 6 90 15 1 Grd 3 rash, anorexia *All received CYC (50 mg/m2) PO once daily.

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

Background:Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial.Methods:Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured.Results:Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers.Conclusion:This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma

The purpose of this study was to evaluate the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone (CP) as a salvage therapy for multiple myeloma (MM). A total of 27 consecutive patients with MM received a treatment regimen that consisted of oral cyclophosphamide 50 mg and prednisone 15 mg daily. Nineteen patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy as a result of severe infection associated with the conventional chemotherapy. Patients had received 1 to 4 chemotherapeutic regimens before the enrollment. The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival (PFS) has not been reached. In the nonresponding patients, the median PFS was 4 months. Continuous low-dose CP is an effective and well-tolerated salvage therapy for MM.

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma.

Abstract 4962 ObjectiveTo assess the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone regimen (CP) as a salvage therapy for multiple myeloma (MM). MethodThe CP regimen consisted of oral cyclophosphamide at 50 mg and prednisone at 15 mg daily. A total of 27 consecutive patients received the CP regimen: 19 patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy due to severe infection associated with conventional treatment. All patients had received 1-4 chemotherapeutic regimens prior to the current study. ResultThe overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival has not been reached. In the non-responding patients, the median progression-free survival was 4 months. In patients with severe comorbid conditions and unwilling to accept conventional chemotherapy because of severe infection, the physical conditions improved significantly. ConclusionContinuous low-dose CP regimen is an effective and well-tolerated salvage therapy for MM. DisclosuresNo relevant conflicts of interest to declare.

Antiangiogenic effect of continuous low-dose chemotherapy on Lewis lung carcinoma

Recently a number of preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved by metronomic-dosing (low-dose) protocols. This new target may have some advantages in avoiding toxicity and resistance caused by chemotherapeutic drugs. This study is to test the efficacy of continuous low-dose cyclophosphamide (CTX) for antiangiogenic effect on Lewis lung carcinoma, and investigate its antitumor effect and toxicity. C57/BL6 mice bearing Lewis lung carcinoma were randomly divided into three groups, receiving low-dose metronomic (LDM) CTX, maximum tolerated dose (MTD) CTX therapy and saline respectively. Tumor growth, weight loss, peripheral white blood cell counts and survival of mice were monitored in each group. At the end of experiment, tumors were resected for immunohistochemical staining. Tumor microvascular density (MVD) and vascular endothelial growth factor (VEGF) level were detected by immunohistochemical staining. MVD and VEGF expression of tumors were much lower in the mice received LDM CTX therapy than those in control group and MTD CTX group (P < 0.05). During the experiment, growth delays of tumor were found in the mice received LDM CTX therapy, without apparent body weight loss or leukopenia, and the survival of mice was remarkably prolonged, compared with mice received MTD CTX therapy (P < 0.05). The continuous low-dose regimen of CTX can significantly increase the therapeutic activity with decreased toxicity and prolonged animal survival for lung cancer. It may act as an antiangiogenic and lead to less drug resistance.

Combination therapy with vinorelbine plus continuous low-dose cyclophosphamide may have activity against childhood sarcomas,

Combination therapy with vinorelbine plus continuous low-dose cyclophosphamide may have activity against childhood sarcomas,

A Case of Intracardiac Lymphoma as a Presentation of Non Hodgkin's Lymphoma.

Lymphomatous involvement of the heart is extremely rare at initial diagnosis and presentation of malignant lymphoma. Worldwide, only a few cases have been diagnosed and treated during life and only four cases were diagnosed before death in Korea. We report a case of non-Hodgkin's lymphoma with two right atrial masses detected by chest computed tomography and transesophageal echocardiography. The patient was an 80 year- old man and the presenting symptoms included generalized weakness, weight loss, constipation and low abdominal pain. For diagnosis, the mass of the perinephric area was biopsied under ultrasonographic guidance, and pathologically it was determined to be malignant lymphoma, diffuse large B cell type. The patient was treated with continuous low dose cyclophosphamide and prednisolone vice standard chemotherapy because of advanced age and renal dysfunction. After 2 months of treatment the masses in the atrium and the intraabdominal masses disappeared.

Continuous low-dose cyclophosphamide–prednisone is effective and well tolerated in patients with advanced multiple myeloma

Background: Multiple myeloma is an incurable disease and after several lines of chemotherapy, patients enter a phase in which no standard treatment options are available. The poor outlook of these patients requires mild, palliative therapy with low toxicity. Previously used regimens either require frequent hospital attendance, lack efficacy or have significant toxicity.Methods: In the current study, daily low dose, oral cyclophosphamide (100 mg) and prednisone (10–20 mg; CP) were administered to patients with advanced myeloma. Forty-two patients with progressive disease after melphalan-based and VAD treatment were enrolled.Results: Objective responses were observed in 29 of 42 (69%) patients. In responding patients, median overall survival and progression-free survival were 22.2 months and 15.0 months, respectively. In non-responders, median OS was 3.5 months only. Side-effects were limited. Cytopenia was the most frequent event (8/29) prompting dose reduction. CP had to be stopped permanently in four patients (two cytopenia, two infections).Conclusion: Orally administered, low dose continuous CP is a feasible, effective and well-tolerated regimen in the management of advanced multiple myeloma.

Continuous low-dose cyclophosphamide (NSC-26271) therapy in advanced ovarian cancer

A low dose, continuous treatment by cyclophosphamide ( 100 mg/day p.o.) has been given to 141 patients with documented Müllerian ovarian cancer. From this total 134 have been evaluated for drug related toxicity. Response and survival have been studied in 72 patients in stages III, IV or in recurrence, all with at least one measurable tumor mass. Results demonstrate that this regimen of administration induces remission and prolongation of median survival with a very low level of toxicity and minimal discomfort to the patient.