Cyclosporin A as an Immunosuppressive Treatment Modality for Patients with Refractory Autoimmune Thrombocytopenic Purpura after Splenectomy Failure

The treatment of autoimmune thrombocytopenic purpura (AITP) remains unsatisfactory in patients refractory to first-line management such as corticosteroid therapy and/or splenectomy. Patients with refractory AITP usually require unacceptably high doses of corticosteroids to maintain a safe platelet count. Immunosuppressive treatment with cyclosporin A (CsA) is a relatively new treatment modality, and no large studies of this drug have been conducted. We used CsA in 6 patients with refractory AITP who had platelet counts of less than 20 x 10(9)/L without any therapy or who had evidence of subcutaneous and mucosal bleeding. All 6 patients had undergone splenectomy. When CsA therapy was begun, 5 of the patients were receiving methylprednisolone (MP) at a daily dose of 32 mg or greater. During the following months, the MP dosage was tapered, or the drug was withdrawn. Three patients achieved a complete remission (CR), whereupon CsA treatment was gradually discontinued. Two of these 3 patients later relapsed, but both responded to an additional course of CsA and achieved a second CR. The remaining 3 patients achieved a partial remission (PR). One patient, a woman with an AITP history of more than 30 years, obtained a stable PR with a platelet count substantially greater than 20 x 10(9)/L, which was successfully maintained by low doses of CsA and MP. The most frequent side effect of CsA therapy in our patients was a painful edema of the lower extremities. Our experience shows that CsA is a safe and effective treatment option for patients with refractory (chronic) AITP. It may be given at a low dose as maintenance therapy, and remissions may be sustained even after the drug has been discontinued.     

Safety and efficacy of intravenous pulse cyclophosphamide in acute steroid refractory inflammatory bowel disease

BACKGROUND AND AIMS: One major problem in the management of steroid refractory attacks of patients with inflammatory bowel disease (IBD) is the establishment of a rapidly acting immunosuppressive regimen. Based on its well known efficacy in systemic vasculitis, intravenous cyclophosphamide pulse therapy was used in refractory IBD patients to evaluate both its efficacy and safety. METHODS: Between December 1998 and May 2001, seven patients (Crohn's disease, n=5; indeterminate colitis, n=1) with severe steroid refractory IBD (Crohn's disease activity index (CDAI) 264-479 points) received 4-6 cycles of monthly treatment with intravenous cyclophosphamide (750 mg) in a prospective uncontrolled pilot study. RESULTS: All patients improved after two intravenous pulses of cyclophosphamide and six of seven patients achieved complete remission (CDAI <150 points). One patient with Crohn's disease of the small and large bowel showed an impressive clinical response but did not enter into remission. Tapering to low dose steroids was possible in all responders. Remission was maintained in all patients for 18 months (median) but required a second course of intravenous pulse cyclophosphamide in one patient. The drug was well tolerated except for two episodes of candida oesophagitis. CONCLUSIONS: Intravenous pulse cyclophosphamide may be a safe and effective treatment in patients with severe IBD unresponsive to steroid treatment and merits evaluation in a controlled trial.     

Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to conventional therapy

BACKGROUND AND OBJECTIVES: In recent years fludarabine alone or in combination with other drugs has been reported to be effective in the treatment of B-cell chronic lymphocytic leukemia (B-CLL), both as first line and salvage therapy. Among the different combination regimens, the association of fludarabine and cyclophosphamide has shown a considerable therapeutic efficacy, although a relevant number of infectious complications have been described, particularly in elderly patients. The aim of this work was to evaluate the efficacy, the toxicity, and the incidence of infectious episodes of a regimen combining lower doses of fludarabine and cyclophosphamide in elderly patients with B-CLL refractory to conventional therapy. DESIGN AND METHODS: Twenty patients with progressive B-CLL with a median age of 75 years (4 in stage B and 16 in stage C) and refractory to conventional therapy were enrolled in this study. The combination regimen was as follows: fludarabine 15 mg/m2/day i.v. [max 25 mg] and cyclophosphamide 200 mg/m2/day i.v. for four days. RESULTS: All patients enrolled were evaluable for response. Three out of 20 (15%) patients achieved a complete remission (CR), 14/20 (70%) a partial response (PR) with an overall response rate (CR+PR) of 85%, according to National Cancer Institute-Working Group response criteria. Three patients were considered resistant. In four out of 20 patients (20%), a severe neutropenia (neutrophils < 0.5x10(9)/L) occurred and one of them developed an infectious complication which required treatment with systemic antibiotics and granulocyte colony- stimulating factor (G-CSF). Non-hematologic toxicity was negligible in all patients but one, who despite a adequate therapy with allopurinol and hydration, experienced a tumor lysis syndrome with transient but severe renal impairment. INTERPRETATION AND CONCLUSIONS: The association of low-dose fludarabine and cyclophosphamide appeared to be effective in this subset of B-CLL patients, reproducing a similar overall response rate obtained with other fludarabine-based combination therapies. In addition, in this group of elderly patients, toxic side effects were negligible and infectious complications remarkably low.     

Late spontaneous remissions in severe adult autoimmune thrombocytopenia

We report on four cases (three women, one man, age at diagnosis 26–61 years) with severe autoimmune thrombocytopenia (AITP) who were refractory to initial steroid therapy (n = 4), to subsequent splenectomy (n = 2), azathioprine (n = 1), and cyclosporine (n = 1). Over years they received low-dose continuous or intermittent steroid therapy. After 6 to 31 years these patients achieved a “spontaneous” complete remission (CR) (n = 3) or partial remission (PR) (n = 1) unrelated to any specific second or third line treatment; CR/PR are sustained for 0.5+ to 9+ years. These data indicate that spontaneous remissions may occur in AITP even after a long duration of the disease.     

Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide

BACKGROUND: Active anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is commonly treated with cyclophosphamide, a drug with serious side effects, and with corticosteroids. OBJECTIVE: To determine the efficacy of a possible alternative drug for cyclophosphamide, oral mycophenolate mofetil (MMF) 1000 mg twice daily and oral prednisolone 1 mg/kg once daily as remission induction treatment. METHODS: 32 consecutive patients with 34 episodes of active vasculitis who could not be treated with cyclophosphamide were diagnosed for a median (range) of 6.0 (0.3-22) years and experienced 4 (0-14) relapses prior to the current episode. Treatment response and relapse-free survival were analysed. RESULTS: Complete remission (CR) was obtained in 25 (78%) patients, partial remission (PR) in 6 (19%), whereas 1 (3%) patient did not respond. 19 patients relapsed, 13 (52%) after CR, 14 (3-58) months after starting the treatment and 6 (100%) after PR, 6 (2-10) months after starting the treatment. The median relapse-free survival was 16 months, comparable with the interval between the previous relapse and the current MMF-treated relapse (17 (3-134) months). Relapse-free survival at 1, 3, and 5 years was 63%, 38% and 27%, respectively. Patients who had been treated successfully with cyclophosphamide before responded better (CR 84%, relapse 50%) than those who had not (CR 50%, relapse 100%). Minor gastrointestinal side effects and infections occurred frequently. MMF was prematurely discontinued due to adverse effects in two patients. CONCLUSION: MMF, in combination with prednisolone, can induce remission in patients with relapses of AAV intolerant to cyclophosphamide.     

Phase II study of sorafenib in patients with relapsed or refractory lymphoma

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.     

Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate

Imatinib mesylate, an inhibitor of the Bcr-Abl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib mesylate followed by imatinib mesylate-based consolidation/maintenance therapy. Of these patients, 11 had de novo disease, 4 were primary failures after induction (without imatinib mesylate), and 5 were in complete remission (CR) after induction (without imatinib mesylate). All 15 patients treated for active disease achieved CR. Within a median of 3.5 months in first CR, 10 patients underwent allogeneic stem cell transplantation (SCT). One patient relapsed after matched related SCT. The other 9 patients remained alive in CR with median follow-up of 12 months after SCT (range, 1+ to 17+ months). Among 10 patients ineligible for (no donor or older age) or refusing allogeneic SCT, 1 patient relapsed after one year. There were 5 patients who remained alive in continuous CR for a median of 20 months (range, 4+ to 24+ months), with 2 older patients dying in CR at 15 and 16 months of comorbid conditions. Molecular CRs were achieved in both groups (SCT or no SCT). Outcome with hyper-CVAD and imatinib mesylate appears better than with prior regimens; continued accrual and longer follow-up of the current cohort is needed.     

Efficacy of an early intensification treatment integrating chemotherapy, autologous stem cell transplantation and radiotherapy for poor risk primary mediastinal large B cell lymphoma with sclerosis

The aim of our study was to evaluate the impact of an early intensification programme including chemotherapy (CHT), autologous stem cell transplantation (ASCT) and radiation therapy (RT) in patients with primary mediastinal large B cell lymphoma (MLCL) with sclerosis presenting with adverse prognostic factors. Between 1993 and 1999, 19 patients with MLCL were referred to our institution. Four patients were classified as low risk according to the age-adjusted International Prognostic Index (AA-IPI). Fifteen (79%) were categorised in the high-intermediate or high risk group and were considered eligible for ASCT. Induction therapy consisted of VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin) for 12 weeks. After induction therapy the four low risk patients achieved a complete remission (CR) and did not undergo ASCT. Of the 15 poor risk patients, five achieved CR, seven partial remission (PR), and three showed refractory disease (RD). All these patients received mobilising therapy consisting of high-dose cyclophosphamide. After peripheral stem cell (PSC) collection, to obtain a greater tumor mass reduction before transplantation, the seven patients in PR underwent further treatment with high-dose etoposide and those with RD received two cycles of DHAP (dexamethasone, cytarabine and cisplatin). At the time of ASCT, seven patients were in CR, six in PR and two had RD. After transplantation using BEAM as preparative regimen, all patients but one achieved a CR. Seven patients with minimal (<25%) residual mass at computed tomography scan received further mediastinal RT even if they had a negative Ga(67) scan. At a median follow-up of 35 months from transplantation the disease free survival is 93%. The outcome following this programme of early intensification in poor prognosis MLCL results in a high incidence of durable remissions even in patients with refractory disease.     

Autologous stem cell transplantation for advanced Hodgkin's disease in children. Spanish group for BMT in children (GETMON), Spain

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkin's disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): n = 12; further CR (CR >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5-34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31-34.     

CTD方案治疗难治或复发多发性骨髓瘤

目的应用环磷酰胺、沙立度胺及地塞米松(CTD)方案治疗难治或复发多发性骨髓瘤(MM)。方法20例难治或复发MM患者接受沙立度胺,100~200mg/d,口服持续应用;环磷酰胺,200~300mg.m-2.d-1,1~4d,静脉注射;地塞米松,20~40mg/d,1~4d,口服。4周为1个疗程。3个疗程后,若出现疗效或病情稳定则再连续应用3个疗程;若病情进展,则停止治疗。结果3个疗程后,13例(65%)患者显示治疗反应,其中9例患者获部分缓解,4例患者获微小缓解。而5例患者病情稳定,2例进展。对病情未进展的18例患者继续治疗3个疗程后再次评价,则部分缓解13例(65%),获微小缓解5例。结论CTD是一个具有较好治疗前景的方案。     

Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial.

OBJECTIVE: To evaluate the efficacy of intravenous cyclophosphamide pulse therapy in patients with optic neuritis associated with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Ten consecutive patients with optic neuritis due to SLE whose condition was refractory to corticosteroids and oral immunosuppressants were treated with intravenous cyclophosphamide (0.5 to 1.0 g/m2) monthly for 6 months. RESULTS: All patients had bilateral eye involvement. One eye was legally blind, and 13 eyes could see only hand movements or count fingers. Six patients had evidence of the secondary antiphospholipid antibody syndrome. Complete recovery in visual acuity occurred in 10 eyes (50%), and a partial response occurred in six eyes (30%); four eyes (20%) had no response. Complete response in the field tests occurred in eight eyes (40%), with a partial response in nine eyes (45%); no improvement occurred in three eyes (15%). CONCLUSIONS: Intravenous cyclophosphamide pulse therapy seems to be an effective treatment for optic neuritis refractory to corticosteroids, oral immunosuppressants, or both. A randomized controlled trial will be necessary to confirm our results.     

Recombinant interferon-alpha-2b treatment of hairy-cell leukaemia: experience with a low-dose schedule

50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha-2b 2.0 x 10(6) IU/m2 subcutaneously three times weekly to evaluate the efficacy of low-dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN-alpha-2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82%) patients showed CR or PR, 9 patients (32%) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN-alpha-2b is a highly effective first-line therapy for HCL.     

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.     

Flexible Low-Intensity Combination Chemotherapy for Elderly Patients with Acute Myeloid Leukemia

Twenty-five patients aged 57 to 88 years (median, 70 years) with acute myeloid leukemia were treated with a flexible low-intensity treatment regimen comprising mitozantrone (mitoxantrone) 6 mg/m2 administered by intravenous infusion x3 days, cytarabine 10 mg/m2 subcutaneously every 12 hours x7 to 14 days, and etoposide 100 mg orally x7 to 14 days. Seventeen of these patients had a preexisting myelodysplastic syndrome. The clinical response was correlated to the results of cytogenetic studies (23 patients) and of viability studies of leukemic blasts (7 patients). Eleven of the 25 patients achieved complete remission (CR), 8 achieved partial remission (PR), and 4 showed no response. There was 1 toxic death, and 1 patient died soon (1 week) after presentation. Treatment was well tolerated. Although myelotoxicity occurred regularly, the recovery time was < or = 3 weeks for most of the responding patients. Duration of survival for patients who had CR has ranged from 4+ to 43+ months and for patients who had PR, 3 to 16 months. Irrespective of the remission status (CR or PR), responding patients with favorable (n = 1) or intermediate (n = 10) cytogenetic findings had a significantly better survival time (median, 14 months) than did those with unfavorable (n = 7) cytogenetic findings (median, 5 months). In vitro studies showed a progressive reduction in the number of circulating blasts. The number of viable blasts 3 days after initiation of therapy appeared to give an early indication of clinical response. Treatment with a flexible low-intensity protocol seems to achieve results comparable with those reported for intensive antileukemia therapy and has much less toxicity.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD).METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800mg) per month.RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d).CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD). METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800 mg) per month. RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d). CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Acquired factor VIII inhibitors in non-haemophilic patients: clinical experience of 15 cases

We retrospectively analysed 15 non-haemophilic patients with acquired factor VIII inhibitors seen in our regional haemophilia centre. The median age was 55 years (range: 21-80). About 70% of patients older than 50 were male, while all five patients younger than 50 were female. The most common underlying condition was pregnancy or postpartum status (20%). About 27% of cases had no identifiable underlying condition. About 27% of patients had medical conditions that were unlikely to be related to acquired inhibitors. The most frequent presenting symptom was spontaneous haemorrhage of soft tissues, skin or joints. Twelve of 13 (92.3%) evaluable patients achieved complete remission (CR) with prednisone alone and/or combined prednisone and cyclophosphamide, but their clinical courses were highly variable. The median time to response was 21.5 weeks (range: 2-176) and the median treatment duration was 9 months (range: 1.25-66). All six patients treated with prednisone initially, and then combined prednisone/cyclophosphamide if no response (NR) to prednisone within 3-4 months (three patients), achieved CR; while four of five patients treated initially with combined prednisone/cyclophosphamide had CR. Patients older than 50 years had a similar response rate, median time to response and median treatment duration as did patients younger than 50 years (83% vs. 100%; 21.5 vs. 32 weeks, and 8 vs 16.5 months, respectively). Furthermore, the differences in the median time to response and treatment duration for patients with high or low baseline or peak inhibitor titres were negligible. Only one patient died of a treatment-related pulmonary aspergillosis 18 months after an acquired inhibitor was diagnosed. None of these patients died of bleeding complications. In conclusion, our patients with acquired FVIII inhibitor had highly variable clinical courses and responses to steroid or immunosuppressive therapy. The inhibitors in the majority of patients resolved in less than 6 months although in two cases it persisted for longer than 1 year before resolving. Treatment with prednisone alone as first line, then combined prednisone with cyclophosphamide if NR to prednisone seemed equally effective when compared with using combined prednisone and cyclophosphamide initially. Further studies of newer therapeutic agents such as 2-chlorodeoxyadenosine (2-CDA) and rituximab are warranted for patients refractory to conventional immunosupressive therapy.     

Sequential intermediate-dose cytosine arabinoside and mitoxantrone for patients with relapsed and refractory acute myelocytic leukemia

Based on in vitro evidence of time-dependent synergistic kill of HL-60 leukemia cells exposed to Ara-C and mitoxantrone, 44 patients with relapsed or refractory AML and 3 with blastic CML were treated with a timed sequence of both drugs. There were 25 females and 22 males, with a median age of 53 (range 21-75). Of 31 patients with relapsed AML, 24 had one prior remission, 6 had two and 1 had three. Of these, 15 had failed a second reinduction attempt. Thirteen patients were primarily refractory to induction with Ara-C plus daunorubicin. Each dose of Ara-C, 500 mg/m2, was followed after 6 hr by mitoxantrone, 5 mg/m2, and the sequence was repeated four to six times (44-68 hr) in different cohorts of patients. All but two patients (one with blastic CML and one in relapse and refractory) are evaluable for response and toxicity. Of 16 patients in relapse without prior reinduction 7 achieved CR and 3 PR (62% response rate); there were 3 CR in the 14 patients who were in relapse and refractory (21% response rate) and 4 CR and 1 PR (35% response rate) in the 14 patients with primary anthracycline resistance. Five of seven patients previously exposed to mitoxantrone achieved CR. Response lasted from 2 to 42 months, with two patients alive and in continuing remission at 34 and 42 months. Average marrow recovery was seen after 25 days and time to remission was 30 days. Six patients died in induction (four from sepsis and two from the tumor lysis syndrome) and 21 had progressive disease. Chemotherapy was well tolerated with minor nausea and vomiting in 13 patients, moderate in 20, and severe in 2. Most patients did not have evidence of drug-induced mucositis: it was minor in 9 and moderate in 2. Renal dysfunction was attributable to the use of nephrotoxic antibiotics. Hepatic dysfunction was reversible and was minor in 10 patients, moderate in 13, and severe in 3. Sequential, timed administration of intermediate-dose Ara-C and mitoxantrone is an active and well-tolerated antileukemic regimen.     

Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) who had relapsed after a complete remission induced by an Adriamycin-containing chemotherapy regimen participated in this prospective pilot study. The patients ranged in age from 16 to 60 years (median 42 years). All patients received dexamethasone, high-dose cytarabine, and cisplatin (DHAP) for two courses at 3- to 4-week intervals. Patients achieving a partial or complete response were scheduled to receive involved-field radiotherapy and high-dose carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (ABMT). Among 48 evaluable patients (ie, 1 was lost to follow-up and 1 had no measurable disease) 7 patients obtained a complete response (CR) and another 21 patients achieved partial response (PR), whereas the remaining 20 patients failed. One responder died of treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and was submitted to ABMT. Twenty-two patients underwent ABMT [20 with BEAC and 2 with cyclophosphamide plus total body irradiation (TBI)] of whom 2 (9%) died of toxicity and 10 relapsed. One patient was a suicide at 28 months post-ABMT in CCR and 9 are alive disease-free 24 months to 32 months (median 30 months) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documents the ability of DHAP followed by ABMT to produce durable complete remission in a significant proportion of patients with relapsed aggressive NHL. Forty-four percent of all patients with relapsed lymphoma who entered the study actually underwent ABMT and 20% of the total group are projected to be long-term disease-free survivors.     

Rituximab (anti-CD20 monoclonal antibody) as consolidation of first-line CHOP chemotherapy in patients with follicular lymphoma: a phase II study

Advanced stages of follicular lymphoma are deemed incurable by conventional approaches. Immunotherapy with the humanised monoclonal anti-CD20 antibody rituximab represents a new therapeutic option. The aim of our study was to determine the effectiveness and safety of rituximab in the consolidation setting of first-line treated patients with follicular lymphomas. Thus the goal was first to reduce tumour burden using the CHOP regimen as induction treatment followed by consolidation with rituximab administered on a standard 4 wk schedule at a dosage of 375 mg m-2 body surface area. Between August 1998 and April 2001, 41 patients were enrolled in the study. All patients were evaluable with regard to tumour response and toxicity. The overall remission rate in the intent-to-treat analysis was 100%. On subgroup analysis, 20 [83% (95% CI: 63-95%)] of the 24 patients with grade 1 or 2 histology entered complete remission (CR), in 10 cases (42%) after additional rituximab therapy. Rituximab thus led to CR in 10/14 patients [71% (95% CI: 42-92%)] who had merely achieved partial remission (PR) with CHOP. Of 16 evaluable patients with grade 3 histology (excluding one patient achieving CR on CHOP who refused further treatment with rituximab), 15 [94% (95% CI: 63-97%)] achieved CR, 13 (81%) of these while still receiving CHOP. Two of the three patients achieving only PR on CHOP entered CR following rituximab. Thirty-four patients (83%) continued to be in remission during a median follow-up period of 24.3 (9-40) months. Our data suggest that the use of rituximab for consolidation after CHOP may improve CHOP-induced remission and thus increase the CR rate. Furthermore, it was accompanied by a reduced rate of infusion-related side-effects.