Emanuel Jacky

Prognostic index for adult patients with acute myeloid leukemia in first relapse

PURPOSE The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML. PATIENTS AND METHODS A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials. RESULTS Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years). CONCLUSION The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.

Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies.

PURPOSE The aim of this prospective randomized trial was to examine the efficacy and safety of filgrastim after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Patients with poor-risk non-Hodgkins lymphoma or relapsed Hodgkins disease were treated in a randomized, open-label trial to study the use of filgrastim as an adjunct to high-dose chemotherapy and ABMT. Of 43 assessable patients, 19 were randomized to receive filgrastim by continuous subcutaneous infusion at a dose of 10 micrograms/kg/d, 10 to filgrastim 20 micrograms/kg/d, and 14 to a parallel control group that received no filgrastim after ABMT. RESULTS For all filgrastim-treated patients analyzed together, the median time to neutrophil recovery > or = 0.5 x 10(9)/L after the day of ABMT was significantly accelerated to 10 days compared with 18 days in control patients (P = .0001). The median number of platelet transfusions was identical in both groups. Clinical parameters, including the median number of days with fever (1 v 4, P = .0418) and neutropenic fever (5 v 13.5, P = .0001) were significantly shorter in the filgrastim than in the control group. The number of days on intravenous antibiotics and duration of hospitalization were also shorter in the treated groups; however, the differences did not reach statistical significance. For patients treated with the two different dose levels of filgrastim, the neutrophil recovery and clinical results were similar. Filgrastim-associated toxicity appeared to be minimal, with five adverse events considered at least possibly related to filgrastim: two in the higher-dose group and three in the lower-dose group. All of these were rated moderate, except one case of severe bone pain that did not preclude continued filgrastim treatment at a lower dose. Survival and relapse-free survival were similar for control and filgrastim-treated patients. CONCLUSION Taken together, the results of this first randomized study support the role of filgrastim given as an adjunct to ABMT in accelerating neutrophil recovery, as well as in reducing treatment-related morbidity and overall duration of the treatment procedure.

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

Criteria for defining a complete remission in acute myeloid leukaemia revisited. An analysis of patients treated in HOVON-SAKK co-operative group studies

Complete remission (CR) in patients with acute myeloid leukaemia (AML) is the primary endpoint for the evaluation of induction treatment and treatment strategies. However, the choice and application of the criteria for a haematological CR can often become a subject of debate because of regeneration more than 5% blasts may be present at the time of response evaluation; platelet and neutrophil recovery may be incomplete and marrow cellularity can vary. This study examined the individual parameters for CR in 1250 adult patients with de novo AML treated according to three successive study protocols. Patients with ≤5% blasts showed the best overall survival (OS) and the lowest relapse risk (RR). This was independent of blast cells present in the peripheral blood or bone marrow (BM) cellularity. In the same patient group, the presence of extramedullary leukaemia, incomplete platelet (<100 × 109/l) or neutrophil (<1·0 × 109/l) recovery caused a reduced OS and increased RR. In conclusion, ≤5% blasts in the BM, recovery of neutrophils and platelets, and the absence of extramedullary disease constitute the cornerstones for the definition of a haematological CR in patients with AML.

False-positive human serum chorionic gonadotropin in a patient with a history of germ cell cancer.

Tumor markers, including the β-subunit of human chorionic gonadotropin (β-hCG), and radiological imaging methods are commonly used for the diagnosis and monitoring of testicular cancer. We report of a patient with a history of classical seminoma stage I who had elevated serum levels of β-hCG suggesting relapse 5 years after initial treatment. Radiological evaluation revealed a pericardial cyst, which was surgically removed. Histological evaluation did not demonstrate malignant tissue, suggesting a false-postive β-hCG. Further workup confirmed this suspicion as we could demonstrate false-positive test results due to heterophilic antibodies detectable in the patient’s serum. This case stresses the need for verification of β-hCG levels in patients where clinical results are not in line with laboratory results.

Risk-adapted chemotherapy of germ cell tumors with carboplatin, etoposide and bleomycin for low-risk and cisplatin, etoposide and ifosfamide for high-risk patients. A single-center study.

The prognosis of germ cell tumors treated with chemotherapy depends on the presence of nonseminomatous tumor, clinical parameters based on the tumor volume and site, as well as on the level of the tumor markers AFP, βHCG and LDH. We report here on the results of a risk-adapted approach to the chemotherapy of germ cell tumors. Patients with low-risk tumors, defined as seminomatous disease and/or nonseminomatous disease with a tumor mass <10 cm, less than 20 lung metastases, no liver, bone, or CNS metastases, and levels of AFP <1,000 IU/ml and βHCG <10,000 IU/l, were to receive 4 cycles of carboplatin 400 mg/m2 i.v. day 1, etoposide 120 mg/m2 i.v. days 1–3 and bleomycin 30 IU i.v. days 1, 8 and 15 during the first 3 cycles (CEB90). Patients with high-risk disease were to receive 4 cycles of ifosfamide 1,500 mg/m2 continuous infusion on days 1–4 together with mesna 1,200 mg/m2 days 1–5, cisplatin 20 mg/m2 i.v. days 1–5 and etoposide 100 mg/m2 i.v. days 1–5 (VIP). Of the 60 patients treated with this risk-adapted approach, 51 had low-risk and 9 had high-risk disease. Forty-five of 51 patiens treated with CEB90 achieved complete remission (CR), 4 achieved partial remission with marker negativity. Four patients with CR relapsed between 4 to 8 months after the start of chemotherapy. Of the 6 patients failing CEB90, 3 were treated successfully with surgery or further chemotherapy. With a median follow-up of 52 months, the estimated cause-specific 3-year survival is 93% (95% confidence interval, CI, 80–98%). Seven of 9 high-risk patients treated with VIP achieved a CR and 1 patient relapsed. All 3 patients failing VIP had successful salvage therapy. With a medium follow-up of 63 months all patients remain alive and free of disease. Forty-six patients receiving CEB90 were retrospectively classified to be in the good prognosis group according to the international germ cell consensus classification. Their estimated 3-year survival was 95% (CI 81–99%). We thus confirm that CEB90 is a well-tolerated outpatient regimen with good results in good prognosis germ cell tumors. Bleomycin at a cumulative dose of 270 U might contribute substantially to the inferior effect of carboplatin as compared to cisplatin. However, in view of the results of randomized studies favoring cisplatin over carboplatin, it is not recommended to use this regimen outside a clinical trial.

Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors.

durable complete remission (rate, 57%) after dose-intense sequential, accelerated chemotherapy with paclitaxel ifosfamide and three cycles of high-dose carboplatin etoposide (mean target carboplatin area under the curve [AUC] of 24 [mg/mL] minute per cycle) followed by peripheral blood-derived stem-cell support in patients with cisplatin-resistant germ cell tumors. Hearing impairment or deafness were not reported as adverse effects. Carboplatin-induced ototoxicity in different high-dose combination regimens has been described by other investigators [2,3]. Between October 2000 and August 2002, we treated nine patients with resistant or recurrent germ cell tumors according to the regimen described by Motzer et al, with three cycles of high-dose carboplatin etoposide (carboplatin AUC of 24 [mg/mL] minute). All patients were pretreated with as many as four cycles of cisplatin-containing chemotherapy. At the beginning of the dose-intense therapy, none of the patients had a clinically obvious hearing impairment. During treatment, all of them started to suffer from hearing disorders and finally developed a clinically manifested hearing impairment. Audiometry revealed bilateral high-frequency sensorineural hearing loss (above 2,000 Hz), with tinnitus in six patients; three of them needed a hearing aid. Hearing impairment was apparent in the other three patients as well, though audiometry was not done. Our experience confirms the favorable results in this group of patients with poor prognosis (five of nine patients are in durable complete remission; complete remission rate, 56%), whereas the ototoxicity observed with this regimen is a considerable adverse effect. Ototoxicity seems to be strongly related to the cumulative carboplatin AUC [3]. High-dose carboplatin is thought to be important to obtain favorable results in patients with relapsed or resistant germ cell tumors. Clinicians should be aware of the possible severe ototoxicity with this regimen, and patients undergoing multiple cycles of carboplatin-containing high-dose chemotherapy should be informed about this relevant toxicity.

A prospective study of risk-adapted therapy for large cell non-Hodgkin's lymphoma with VACOP-B followed by high-dose CBV and autologous progenitor cell transplantation for high-risk patients in remission

Several centres reported a favourable outcome after high‐dose chemotherapy with autologous progenitor cell transplantation in selected patients with high‐risk large cell non‐Hodkgins lymphoma in first remission. Based on these observations, we wanted to prospectively determine the outcome of a risk‐adapted therapy for patients with large cell lymphoma. Patients aged 60 years or less received 12 weeks of VACOP‐B chemotherapy. For high‐risk patients in remission this was immediately followed by high‐dose chemotherapy with cyclophosphamide, carmustine and etoposide and autologous progenitor cell transplantation. High‐risk criteria were defined before the establishment of the International Index and included large cell lymphoma stage III or IV or mediastinal large lymphoma with sclerosis stage II or higher, and the presence of bulky tumours and/or an elevated LDH. 89 patients fulfilled the clinical selection criteria and were entered onto this multicentre study. 82 patients were evaluable after confirmation of large cell histology by pathology review. Of these, 51 were considered to be in the low‐risk group and 31 in the high‐risk group. The 3‐year event‐free survival for all patients was 68%. The 3‐year event‐free survival was 76% for the low‐risk and 55% for the high‐risk group (P = 0.061). Only 22/31 high‐risk patients were able to receive the high‐dose chemotherapy in first remission as intended. In conclusion, although our study demonstrated that a risk‐adapted therapy for large cell lymphoma could be safely administered, the potential impact on outcome of the strategy chosen here is likely to be small.