High-dose melphalan and autologous bone marrow transplant for relapsed acute leukaemia

Summary Seven patients with relapsed acute leukaemia were treated with high-dose melphalan (HDM) followed by the infusion of autologous cryopreserved remission marrow. Toxicy was minimal and all seven patients had a complete response. Four patients are still in unmaintained remission at 14, 13, 10, and 3 months, the first two having received a second course of HDM to consolidate the result. The role of HDM as a form of intensification therapy for patients with acute myeloid leukaemia in first remission should be investigated.     

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study

Objective High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. Patients and methods Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m² from days 1–5, idarubicin (HD-IDA) 40 mg/m² as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 μg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. Results Eleven patients (44%, 95% CI: 23–65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m², plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P = 0.72). IDAol t _1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P = 0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m² of IDA but, although the administered dose (mg/m²) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. Conclusion Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m² of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic. The authors declare that they have no potential conflict of interest.     

High-dose cytosine arabinoside: response to therapy in acute leukaemia and non-Hodgkin's lymphoma

Summary Twenty-six patients with acute leukaemia and 14 with high-grade lymphoma received cytosine arabinoside (ara-C) at a twice daily dose of 2 g/m² administered as a 3-h infusion. Thirty-four patients received 12 doses and six electively received four doses only. Complete remission was achieved in six of seven patients with acute myelogenous leukaemia (AML), one of two evaluable patients with blast crisis of chronic myeloid leukaemia and three of eight patients with acute lymphoblastic leukaemia (ALL). Three further patients with ALL had only minimal bone marrow infiltration after one cycle, toxicity precluding administration of a second. Three patients with AML who received four doses only showed no evidence of response. Four of 14 patients with lymphoma who received 12 doses, entered complete remission. Five additional patients died with minimal residual disease whilst severely neutropenic. A complete and a partial response were seen in two patients with immunoblastic and centrocytic lymphoma respectively who received four doses. These results confirm the activity of high-dose ara-C in patients with AML and suggest that it may also be a potentially useful agent in ALL and high-grade lymphoma, especially as the incidence of CNS toxicity is lower than that reported at higher doses.Presented in part at the Third International Symposium on Therapy of Acute Leukaemia, Rome, December 1982     

High-dose versus standard-dose daunorubicin in induction therapy for young patients with de novo acute myeloid leukaemia: a meta-analysis of randomised trials

Purpose: To compare the efficacy and safety of high-dose versus standard-dose daunorubicin for young patients with de novo acute myeloid leukaemia (AML) using meta-analysis.

Methods: Two trials were taken from 2,481 full-text articles. Heterogeneity was assessed using the I² index. Quality assessment was performed with the Cochrane Collaboration’s risk-of-bias tool.

Results: The analysis showed that high-dose daunorubicin induction therapy was associated with higher complete remission (CR) rate (n?=?965; RR?=?1.80; 95% CI?=?1.36–2.38; p?I^2?=?0%) and improved overall survival (n?=?1040; HR?=?0.74; 95% CI?=?0.63–0.87; p?=?0.0003; I^2?=?0%) compared with standard-dose daunorubicin. However, there was no significant interaction between treatment efficacy and prognostic category based on cytogenetics (favourable, intermediate and unfavourable) (p?=?0.44, I^2?=?0%).

Conclusion: High-dose daunorubicin therapy could increase CR rate and improve long-term outcome for young patients with de novo AML. However, further study is needed to identify those who can benefit from high-dose daunorubicin.     

High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia.

BACKGROUND: Liposomal encapsulation of daunorubicin (DaunoXome, DNX; Nexstar Pharmaceutical, Boulder, CO) changes the pharmacology profile to increase delivery to tumor sites and decrease toxicity. The authors investigated the effect of daunorubicin in combination with ara-C in patients with refractory or recurring acute myelogenous leukemia (AML). PATIENTS AND METHODS Sixty-two patients with refractory or recurring AML received escalating doses of daunorubicin of 75, 100, 125, or 135 mg/m(2) daily for 3 days together with ara-C 1 g/m(2) intravenous continuous infusion daily for 4 days. RESULTS: Eighteen patients (29%) achieved a complete remission (CR) and 7 (11%) a hematologic improvement (i.e., met all criteria for CR except for platelet count < 100 x 10(9)/L) for an overall response rate of 40%. The dose-limiting toxicity was mucositis in 4 in 9 (44%) patients treated at the 150 mg/m(2) dose level, but minimal at 125 mg/m(2) (2 of 32, 6%) or 135 mg/m(2) (1 of 13, 8%). Cardiotoxicity Grade 2 was observed in 4 patients (6%) and Grade 3 or higher in 4 patients (6%). The median CR duration was 63 weeks, and overall survival rate was 25 weeks, with 28% patients alive after 1 year. CONCLUSIONS: The combination of DNX (or liposomal daunorubicin) and ara-C has significant antileukemia activity with acceptable toxicity. Further studies are warranted to investigate the role of high-dose anthracyclines in frontline AML therapy.     

High-dose cisplatin in the outpatient clinic: a feasibility study

A clinical trial was undertaken to assess the feasibility of treatment with high-dose cisplatin on an outpatient basis. Eleven patients entered the study: 9 patients with squamous cell carcinoma of the head and neck, 1 patient with malignant melanoma of the skin, and 1 patient with breast cancer. All patients were pretreated. The chemotherapy scheme consisted of cisplatin, 60 mg/m2 for 3 consecutive days, every 4 weeks. We observed 5 partial responses, 4 stable diseases, and 1 progression of disease; 1 patient failed due to toxicity. The overall response rate was 45.4%. This treatment was associated with severe toxicity including nausea and vomiting, myelosuppression, neurotoxicity, nephrotoxicity and electrolyte disorders. Two patients died and 2 discontinued the treatment due to toxicity. In light of the incidence and severity of toxicity, this treatment should not be used as routine practice.     

High-dose amsacrine (AMSA) therapy of relapsed and refractory adult acute nonlymphocytic leukemia. A phase II study

Amsacrine (AMSA) has been shown to be an effective therapeutic agent in the treatment of adult acute nonlymphocytic leukemia (ANLL). The Eastern Cooperative Oncology Group studied the efficacy and toxicity of high-dose amsacrine (200 mg/m2/day for 5 days) in 38 adult patients with refractory and relapsed ANLL. The complete remission rate was low (8%). This dose level of amsacrine caused severe mucositis in 24% of patients and marked liver function abnormalities in 11%. Seizures did not occur, and two reversible cardiac events were not clearly attributable to amsacrine administration. Escalation of amsacrine beyond currently recommended total doses of 600-750 mg/m2 is unlikely to be of benefit.     

High-dose chemotherapy and hematopoietic stem cell transplantation for patients with nasopharyngeal cancer: a feasibility study

BACKGROUND: Nasopharyngeal cancer (NPC) is a highly chemosensitive malignancy. The purpose of this study was to evaluate the clinical efficacy of high-dose chemotherapy (HDCT) in combination with hematopoietic stem cell transplantation in patients with locally advanced or metastatic NPC. METHODS: Nine patients with locally advanced or metastatic NPC were recruited after three to four courses of cisplatin-based chemotherapy followed by a single course of cyclophosphamide 1600 mg/m(2) day 1-4, carboplatin 400 mg/m(2) day 1-3, and thiotepa 120 mg/m(2) day 1-4 or melphalan 120 mg/m(2) day 5. Chemoirradiation was administered after HDCT only if the patient had never received radiotherapy or had residual cervical nodes. RESULTS: A median of 8.32 x 10(6) CD34+ cells/kg was collected. Two patients were rendered disease-free before HDCT, one by massectomy and one by cisplatin-based chemotherapy. All patients recovered rapidly after peripheral blood stem cell transplantation (PBSCT). Among seven assessable patients, response to HDCT was observed in four patients. Only one patient achieved complete response after HDCT. The median time to failure and median survival after HDCT was eight and 18 months, respectively. One patient died of pulmonary hemorrhage two months after transplantation. No long-term disease-free survival was noted. CONCLUSION: HDCT with autologous PBSCT is feasible with an acceptable toxicity, and can convert partial remission into complete remission. While no long-term disease-free survival was observed in this study, further investigations are needed to establish the role of HDCT in the treatment of NPC.     

High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.

PURPOSE: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. PATIENTS AND METHODS: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months). RESULTS: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality. CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.     

High-dose mitoxantrone in acute leukaemia: New York Medical College experience

Based on promising preclinical data, a progressive series of evaluations of the use of high-dose mitoxantrone-based chemotherapy was initiated in acute leukaemia patients. A preliminary phase I study demonstrated that up to 80 mg/m² of mitoxantrone in combination with cytarabine 3 g/m² daily for 5 days could be given as induction therapy to leukaemic patients with acceptable toxicity. Pharmacokinetic data from these patients demonstrated that high concentrations of mitoxantrone were achievable in vivo to levels that were extremely cytotoxic in vitro. Subsequently, in a phase II study, 45 patients with untreated acute myelogenous leukaemia (AML) under the age of 60 received mitoxantrone 80 mg/m² in combination with cytarabine 3 g/m² daily for 5 days and etoposide 150 mg/m² for 3 days. Following this induction, patients received five cycles of consolidation with cytarabine 3 g/m² daily for 4 days with mitoxantrone 20 mg/m² for 1 day on cycles 2 and 4, and etoposide 150 mg/m² for 2 days with cytarabine on courses 1,3 and 5. The patients in this study achieved a complete remission (CR) rate of 80% and a 3-year projected probability of survival of 40%. In a second AML study, 54 adults over the age of 60 with untreated AML were randomized to receive either high-dose or standard-dose mitoxantrone with cytarabine as a single induction regimen without consolidation. Patients receiving high-dose mitoxantrone did not experience increased morbidity or mortality compared with those given lower doses. Comparison of CR rates, disease-free and overall survival consistently favoured high-dose mitoxantrone, although the results did not achieve statistical significance. In patients with acute lymphocytic leukaemia (ALL), high-dose mitoxantrone with cytarabine was given as initial therapy in a phase II study involving 37 previously untreated adults. Results demonstrated that this dose-intensive regimen could produce a high CR rate (84%) with acceptable toxicity and compared favourably with experiences with vincristine/prednisone-based induction regimens. These studies demonstrate that high-dose mitoxantrone can be safely and effectively administered to patients with acute leukaemia and suggest that the incorporation of high doses of mitoxantrone into treatment regimens may lead to enhanced antileukaemic efficacy compared with standard doses. Phase III evaluations are planned.     

High-dose cytosine arabinoside plus etoposide as initial treatment for acute myeloid leukaemia: a single centre study

In a single centre, 52 newly diagnosed patients with acute myeloid leukemia (AML) under the age of 56 years received induction chemotherapy commencing with high-dose cytosine arabinoside (Ara-C) and etoposide (Protocol BF11), followed by Ara-C, 6 thioguanine (6TG). A total of 67% of patients entered remission using these drugs. An anthracycline was added for those patients not in remission. The overall remission rate (CR) was 86.5% (45/52), with a minimum follow-up of 90 days. Patients are hospitalised for relatively short periods, and consequently require less blood product and antibiotic support. Patients in continuing first remission following induction with Ara-C and etoposide are similar in number to those in continuing first remission who initially received an anthracycline. This would imply that the efficiency of Ara-C and etoposide in inducing long-term disease-term survival is comparable with anthracycline-containing regimens. We conclude that high-dose Ara-C and etoposide used in the first induction cycle for treating AML have good antileukaemic effect with acceptable toxicity.     

High-dose therapy including carboplatin adjusted for renal function in patients with relapsed or refractory germ cell tumour: outcome and prognostic factors.

Thirty-one consecutive patients with relapsed or refractory GCT received an HDT schedule including carboplatin, the dose of which was adjusted to measured glomerular filtration rate. There was one HDT-associated death (3%), due to acute renal failure. The 3-year probability of overall and disease-free survival for 21 patients with primary refractory disease or responsive relapse was 60% and 42%, respectively, while none of ten patients with refractory relapse have survived disease free.     

Intra-arterial chemotherapy in patients with breast cancer: a feasibility study.

The aim of this study was to assess the practicality of treating patients with various stages of breast cancer by means of regional (intra-arterial) chemotherapy. Three groups of patients received a median of four (range 2-4) cycles of combination chemotherapy: group I operable primary (n = 10); group II, locally advanced disease (n = 20); group III, recurrent locoregional disease (n = 22). The response rates (complete response, partial response and mixed response) in these groups of patients were 100% in groups I and II and 86% in group III. Morbidity included drug streaming and dysaesthesia in the hand. Patients in groups I and II had their tumours downstaged, allowing surgery to be performed. Local control was also achieved in group III when other treatment modalities had failed.     

High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study.

PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.     

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.     

Posaconazole prophylaxis during induction therapy of patients with acute lymphoblastic leukaemia

Novel treatment schedules of induction therapy for acute lympoblastic leukaemia (ALL) use combinations of immunosuppressive and cytotoxic drugs that are associated with neutropenia and acquisition of invasive fungal infections. It has been described that posaconazole, a triazole antifungal drug, is active against a variety of Candida and Aspergillus species in vitro. Moreover, large clinical trials using posaconazole in severely immunosuppressed patients provided data on efficacy against Aspergillus in vivo. As patients with ALL are also affected by difficult‐to‐treat Aspergillus infections, we conducted a pilot study to prove the safety of posaconazole in patients undergoing intensified induction phase treatment. We report on eight patients receiving prophylactic (200 mg t.i.d.) dose of posaconazole and demonstrate good tolerability of the drug. The most obvious side effect was liver toxicity as defined by abnormal serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase and bilirubin levels (<CTC grade 3) documented in three of eight patients. However, side effects were not life‐threatening and appeared without clear relationship to posaconazole applications. During the study, one patient developed possible aspergillosis of the lung. Therefore, the observations indicate a favourable toxicity profile of posaconazole in ALL therapy. Efficacy of the drug has to be further validated in prospective clinical trials.     

High-dose treatment with autologous bone marrow support as consolidation of first remission in younger patients with acute myelogenous leukaemia

Background:Debate and controversy remain as to the optimalpost-remission therapy for younger patients with acute myelogenous leukaemia(AML). The aim of this study was to evaluate high-dose treatment (HDT) withautologous bone marrow support (ABMS) as consolidation of first completeremission (CR). Patients and methods:One hundred forty-four patients (AML-M3excluded, median age 38 years, range 15–49 years) received remissioninduction therapy comprising: adriamycin 25 mg/m², days 1–3,cytosine arabinoside (ara-C) and 6-thioguanine, both at 100 mg/m²bid, days 1–7. Patients in whom CR was achieved received two furthercycles of the same treatment prior to bone marrow being harvested andcryopreserved. HDT comprised ara-C: 1 g/m² b.i.d. × six daysand total body irradiation (TBI): 200 cGy b.i.d. for three days. Thawedautologous marrow was then re-infused. Results:Complete remission was achieved in 106 of 144 patients(73%) who were thus eligible to receive ara-C + TBI + ABMS; 61 actuallyreceived it. Following HDT, the median time to neutrophil recovery (>0.5× 10⁹/l) was 25 days (range 11–72 days) and to plateletrecovery (>20 × 10⁹/l), 42 days (range 15–159 days).There were eight treatment-related deaths. Analysis by `intention to treat'shows both remission duration (log-rank, P= 0.001) and survival(log-rank, P= 0.004) to be significantly longer for the 106 patientseligible to receive HDT than for a historical control group (n= 133)who received identical remission induction and consolidation therapy butwithout ara-C + TBI + ABMS. With a median follow-up of 5.5 years, 39 of 106patients remain in CR (37%) and 54 (51% of those in whom CR wasachieved) remain alive, with a predicted actuarial survival of 52% at5 years. Conclusions:The addition of ara-C + TBI + ABMS to conventionalconsolidation therapy significantly improved remission duration and survivalover those of a historical control group of patients with AML (aged <50,AML-M3 excluded). HDT was, however, associated with significanttreatment-related mortality and slow blood count recovery. The use of ara-C+ TBI supported by peripheral blood progenitor cells should make the treatmentsafer and more widely applicable in AML.