Courses Of Intensive Chemotherapy Research Articles

Outcome of childhood B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia treated with the Tokyo Children's Cancer Study Group NHL B9604 protocol

From June 1996 to January 2001, 91 patients with B-cell non-Hodgkin lymphoma or B-cell acute lymphoblastic leukemia up to 18 years of age were enrolled in Tokyo Children's Cancer Study Group (TCCSG) NHL B9604 protocol study. Five-day intensive chemotherapy courses including high-dose methotrexate and high-dose cyclophosphamide were used for localized disease (Groups A and B). High-dose cytarabine was added for advanced disease (Groups C and D). Fifteen patients experienced an adverse event. There were three induction failures, eight relapses (three local, four bone marrow (BM), one BM + local), two toxic deaths and two second malignant neoplasm. Event-free survival at 6 years in Group D and in all patients was 82.4% ± 9.2% and 81.9% ± 4.4%, respectively. The TCCSG NHL B9604 protocol achieved an excellent treatment outcome especially in patients with the most advanced disease (Group D: high BM blast cell burden and/or central nervous system involvement).

Caries Experience of Leukemic Children During Intensive Course of Chemotherapy

To determine the incidence of dental caries in 64 leukemic children who received dental treatment before the initiation of chemotherapy and had intensive oral care during the course. Caries experience (deft/DMFT), white-spot lesions (enamel demineralization), premature primary molar extractions and carious first permanent molars were investigated before and after intensive therapy. Pediatric Dental Care Unit and Department of Pediatric Hematology, Faculty of Medicine, Uludağ University. The dental caries level was insignificantly higher following chemotherapy compared to the initial caries level. However the prevalence of white-spot lesions was significantly increased during the course. Caries level in 30 subjects (47%) remained stable. Caries level in leukemic children, who were not caries-free before chemotherapy, could be stabilized by caries prevention methods such as frequent topical fluoride applications and fissure sealants, intensive oral care and improved self-care practices.

Update of the Modified Hyper-CVAD Regimen with or without Rituximab as Frontline Therapy of Adults with Acute Lymphocytic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).

The hyper-CVAD regimen is an effective therapy program for adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following: higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression; and late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) ALL or LL pts were treated on two sequential studies. Burkitt leukemia/lymphoma (BLL) and Philadelphia positive ALL pts were treated on separate protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was eliminated from the second study, with an additional 124 pts were treated (8 courses of intensive chemotherapy). Results were reviewed by lineage (T-cell versus non T-cell), outcome after therapy with rituximab for CD20 positive ALL, and age. Overall CR rate of the group (n=190) was 91%. Median age of the T-lineage pts was 30 (range, 17–74) versus 43 (range, 15–83) for the non-T lineage pts. After a median follow-up of 30 months (range, 6–80), outcome appeared favorable for the younger group aged 30 years or less with 3-year DFS rates of 61% and 66%, and 3-year OS rates of 73% and 71% for non-T and T-lineage, respectively. When comparing outcome of non-T lineage CD20 positive ALL with historical experience, the addition of rituximab appeared to improve DFS rates (56% versus 35%, p=.06) but did not affect survival (62% versus 46%, p=0.23). A subset analysis showed that younger pts aged 30 or less with non T-lineage CD20 positive ALL treated with rituximab had superior outcomes compared with historical experience (DFS rates 62% versus 28%, p=.005; OS rates 73% versus 50%, p=.07). No such benefit of rituximab was observed for the elderly group, in contrast to data previously reported for BLL. Anthracycline intensification appeared to worsen outcome, particularly for T-lineage ALL. Rituximab may benefit subsets of CD20 positive ALL; alternative monoclonal antibodies should be explored. Further improvements in outcome may be achieved with incorporation of novel agents such as nelarabine for T-lineage ALL and sphingosomal VCR for elderly ALL. Modifications to Hyper-CVAD Parameter Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age [≥ 60yrs or poor PS Dose-intensive anthracycline No C2 Liposomal DNR & cytarabine Rituximab No For CD20 ≥ 20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6 or 8 (16 BL) POMP 24 months 30 months Intensifications Months 7, 11 Months 6, 7 & 18, 19

Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.

With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 34 pts have been treated: median age 69.5 (range 61–84); M/F: 21/13; prior AHD: 47%; cytogenetics: good: 1, intermediate: 24, poor: 7, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 56%, failure: 32%, toxic death: 12%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, C. difficile colitis: 1 pt. Of 19 patients in CR, 16 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–14). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died from C. difficile colitis). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 6.8 months (95% CI: 4.5–9.1 months), and median survival is 5.5 months (95% CI: 3.7–7.3 months) for all patients and 10.1 months (95% CI: 4.9–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.

Lung Resection for Invasive Pulmonary Aspergillosis in Neutropenic Patients with Hematologic Malignancies: Long Term Results in Thirty Two Cases.

Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in neutropenic patients. Despite adequate medical treatments, such as amphotericin B or voriconazole, the prognosis of IPA remains poor. Nevertheless, recent studies suggest that the outcome of IPA is improving due to early diagnosis (CT scan, antigenemia), use of new antifungal agents (Azols and Echinocandins), and possibly in some cases to early surgical resection. We here report a retrospective one center study of 32 cases of IPA treated by surgical treatment from 1988 to 2005.Between 1988 and December 2005, thirty-seven consecutive patients underwent lung resection for suspected IPA. They were 22 men and 15 women, with a median age of 49.2 years (15 – 74). The underlying diseases were AML, ALL, aggressive lymphoma and myeloma in 26, 7, 2 and 2 cases, respectively. Surgery was planned after hematologic recovery from the last course of chemotherapy during which IPA was diagnosed, either possible in 18 cases, probable in 18 cases or proven in 1 case (Ascioglu, CID 2002). Surgery consisted in 1 pneumectomy, 6 bilobectomies, 18 lobectomies, 8 wedge resections and 4 lobectomies with wedge resections. No perioperative deaths occurred and the median duration of post surgical hospitalisation was 13 days. Six patients presented surgery related complications: three patients required prolonged pleural drainage, one had a section of the phrenic nerve, one presented a major bleeding and last patient had a pneumopathy. The diagnosis of definite IPA was confirmed in 32 cases. Immediately after surgery, 26 of the 32 patients were able to receive subsequent intensive chemotherapy courses, including 15 stem cell transplant (SCT), either auto (5) or allogenic (10). In all cases, patients subsequently received parenteral antifungal therapy. During these new intensive chemotherapy courses, recurrent aspergillosis was observed in only 2 cases, inducing 1 death from brain localization. Overall, with a median follow-up of 8.3 years (1–18), 40.5% of the patients are alive and the main cause of mortality was relapse, but not IPA.In conclusion, early surgical resection together with antifungal therapy allows definite diagnosis of IPA, prevents from IPA recurrence and early death due to hemotysis, with very few peri-operative complications. All the more, it allows subsequent high-dose chemotherapy to treat the underlying hematologic disease. Surgery might be a treatment of choice to a define group of patient.

Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.

With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 30 pts have been treated: median age 69 (range 60–84); M/F: 17/13; prior AHD: 23%; cytogenetics: good: 1, intermediate: 21, poor: 6, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 59%, progression: 24%, aplastic death: 17%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, c. difficile: 1 pt. Of 17 patients in CR, 15 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–11). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died c. diff). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 5.5 months (95% CI: 3.0–9.8 months), and median survival is 7.6 months (95% CI: 5.7–13.3 months) for all patients and 10.2 months (95% CI: 5.6–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.

Rituximab (Mabthera) Improves the Treatment Results of DHAP-VIM-DHAP and ASCT in Relapsed/Progressive Aggressive CD20+ NHL. A Prospective Randomized HOVON Trial.

A total of 239 patients with relapsed/progressive aggressive CD20+ NHL after/during adriamycin containing regimens, were recruited to the randomized HOVON-44 trial comparing DHAP-VIM-DHAP followed by BEAM and autologous stem cell re-infusion (ASCT)(“DHAP-arm”) with DHAP-VIM-DHAP in conjunction with Rituximab (375 mg/m2) and ASCT (“R-DHAP arm”). Of the included patients, 202 were evaluable and randomized to the DHAP arm (n=101) or R-DHAP arm (n=101). Only patients with CR/PR after two courses of intensive chemotherapy were eligible for ASCT. Patients were well balanced for risk factors. In both arms the majority of patients had not been exposed to Rituximab during first line treatment. As of July 2006, median follow-up of all patients still alive is 24.5 months. After two courses of chemotherapy PR/CR was obtained in 49 % of the patients in the DHAP arm and 77% in the R-DHAP arm (p=<.01;intention to treat analysis). Post-transplantation PR/CR was obtained in 41% and 58% of the patients respectively (p=.40). A significant difference between both arms was observed for failure free survival (FFS), disease free survival (DFS) and overall survival (OS) in favor of the Rituximab arm (p<.05, table 1). The less pronounced difference in OS between both arms is most likely due to the fact that non-responding or relapsing patients in the DHAP arm received salvage treatment with a Rituximab containing regimen. Additionally, a subgroup analysis was performed according to type of response to first-line treatment:1) Response duration more than 3 months (n=138); 2) Progression or response duration less than 3 months (n=64). Within both subgroups, the hazard ratio's for the endpoints were of equal magnitude (.40–.60), indicating that the beneficial effect of Rituximab existed in both subgroups. In conclusion these results demonstrate that the addition of Rituximab to second line of chemotherapy followed by ASCT results in a significant improved FFS, DFS, and OS in patients with relapsed/progressive aggressive CD20+ NHL.Table 1FFSDFSOSDHAP-arm*21%46%48%R-DHAP arm*52%82%62%Hazard ratio.40.32.61p-value log rank test<0.0010.0030.03*: 2 years estimate

Less Toxicity by Optimizing Chemotherapy, but Not by Addition of Granulocyte Colony-Stimulating Factor in Children and Adolescents With Acute Myeloid Leukemia: Results of AML-BFM 98

To improve prognosis in children with acute myeloid leukemia (AML) by randomized comparisons of (1) two short consolidation cycles versus the Berlin-Frankfurt-Muenster (BFM) -type biphasic 6-week consolidation and (2) the prophylactic administration of granulocyte colony-stimulating factor (G-CSF) versus no G-CSF. Further, therapy for standard risk patients was intensified by addition of a second induction, HAM (high-dose cytarabine and mitoxantrone). Four hundred seventy-three patients younger than 18 years with de novo AML were enrolled in trial AML-BFM 98. Patients received five courses of intensive chemotherapy, cranial irradiation, and 1-year maintenance therapy. Four hundred eighteen patients (88%) achieved remission. Compared with trial AML-BFM 93, early deaths decreased from 7.4 to 3.2% (P = .005), and 5-year overall survival increased from 58% to 62% (log-rank P = .03). Both types of consolidation therapy led to similar outcome (event-free survival, 51% v 50%), but in the two-cycle arm, treatment duration was shorter (median duration, 15 days), and treatment related mortality was lower (five v nine patients). G-CSF shortened neutropenia, but did not reduce the rate of severe infections. Intensification of induction therapy did not improve prognosis of standard-risk patients (event-free survival, 62% v 67%). Overall results were improved by neither the administration of G-CSF nor by cycle therapy; however, the latter was easier to perform. Compared with study AML-BFM 93, therapy intensification with HAM in standard-risk patients did not result in improved prognosis. Future treatment designs have to balance intensification of treatment with higher toxicity, improve supportive care, and to consider alternative treatment strategies.

Update of the Modified Hyper-CVAD Regimen with or without Rituximab in Newly Diagnosed Adult Acute Lymphocytic Leukemia (ALL).

Hyper-CVAD is effective therapy for adult ALL [Kantarjian et al, JCO 18:547, 2000; Kantarjian et al, Cancer 101:2788, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone) was alternated with high dose methotrexate and cytarabine every 21 days for 8 courses with G-CSF and prophylactic antibiotics, followed by maintenance with POMP (6-MP, methotrexate, VCR, prednisone). Complete response (CR) rate was 92% with 3-year disease-free survival (DFS) rates 38% overall. A modified hyper-CVAD regimen was developed to address the following: (1) higher induction mortality in patients (pts) aged 60 or older (17% versus 3%); (2) longer DFS reported with early anthracycline intensification; (3) worse survival with CD20 expression (excluding Burkitt's [BL] and lymphoblastic lymphoma [LL] subtypes); (4) CNS relapse rate of 6% and 1% in low and high risk pts, respectively and (5) late relapses after completion of therapy.Modifications to Hyper-CVADParameterHyper-CVADModified Hyper-CVADLaminar air flow roomsNoFor age ≥ 60 yrs or poor PSDose-intensive anthracyclineNoC2 Liposomal DNR & cytarabineRituximabNoFor CD20 ≥ 20Intrathecal treatments4–166–8Maintenance (POMP)2 years3 yearsIntensifications (MTX, asparaginase)Months 7 & 11Months 6,7 & 18,19 with hyper-CVADNewly diagnosed or primary refractory (1 course only) pts were eligible. BL and Ph+ ALL pts were excluded. From May 2000 to December 2001, 77 pts were treated with the modified regimen detailed above (9 courses of intensive chemotherapy). The program was then modified further with elimination of course 2 anthracycline intensification. An additional 80 pts were treated with hyper-CVAD with or without rituximab (8 courses of intensive chemotherapy). The median age for these 157 pts was 40 yrs (range, 15–83) with 20% aged ≥ 60 yrs; 57% were males. Overall response rate was 94% in the evaluable pts (8 too early) with no difference by CD20 expression (49% were CD20+). No induction deaths were observed in the elderly subgroup (2 younger pts with induction deaths). Outcome with anthracycline intensification appeared worse, particularly in the CD20 negative group. The addition of rituximab appeared to improve DFS in CD20 positive group (with or without anthracycline intensification) compared with hyper-CVAD alone (2 yr DFS 90% versus 65%, p=.03); however, overall survival in the CD20 positive group was influenced by deaths in CR (10%) in elderly patients related to GNR sepsis or pneumonia during the intensive phase. Additional accrual and follow-up is needed to further define the role of rituximab in non-Burkitt's adult ALL.

FIP1L1-PDGFRA Positive Secondary Acute Myeloid Leukemia.

The FIP1L1-PDGFRA positive myeloproliferative syndrome (MPS) represents a distinct clinicobiological entity with constitutively enhanced tyrosine kinase activity of the fusion protein and excellent response to treatment with imatinib. Most patients are initially diagnosed as idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia (CEL). A prominent clinical feature besides eosinophilia is the male predominance. However, the natural clinical course remains to be elucidated. Here we report on five male FIP1L1-PDGFRA positive patients (median age 58, range 46–64 years) with various subtypes of acute myeloid leukemia (AML) according to the FAB classification (M0, n=2; M2, n=1; M4eo, n=1; acute eosinophilic leukemia, n=1). All patients had a history of pronounced eosinophilia for a median interval of 6 mo (range 2–186) indicating the presence of a CML-like chronic phase disease evolving to blast crisis or secondary AML. One patient relapsed six years after conventional chemotherapy of a secondary FIP1L1-PDGFRA positive eosinophilia-associated AML M0 with typical features of CEL. Three patients had additional cytogenetic aberrations at diagnosis of AML similar to those frequently observed during clonal evolution of CML (trisomy 8, n=2; trisomy 9, n=1). All five patients received imatinib (100–300 mg/day) for a median time of 12 mo (range 1–23); three patients as monotherapy, one patient after one course and another patient after two courses of intensive chemotherapy. Three AML patients have been treated for more than 3 mo (12+, 18+, and 23+ mo) and are currently free of relapse. All three patients achieved a rapid complete hematological remission, defined as a complete clearance of blasts, normalization of peripheral blood and bone marrow eosinophil count, and a complete molecular remission 4, 5, and 14 mo, respectively, after start of treatment as determined by nested RT-PCR for the FIP1L1-PDGFRA transcript. In all cases treatment with imatinib was well tolerated. We conclude that the occurrence of the FIP1L1-PDGFRA fusion gene seems to be associated with a chronic phase disease which may progress to secondary AML. Therefore, all patients presenting with an eosinophilia-associated AML and normal karyotype should be screened for the cytogenetically invisible FIP1L1-PDGFRA fusion gene by RT-PCR and/or fluorescence in situ hybridization, in addition to the commoner CBFB-MYH11 fusion. Patients with a FIP1L1-PDGFRA positive MPS are excellent candidates for treatment with imatinib even if they present with secondary AML.

Prognostic Significance of High FLT3 Expression Levels in Twenty-Six MDS Patients Examined at Diagnosis and during Disease Outcome.

An internal tandem duplication (ITD) or a point mutation of the FLT3 is detected in about one third of MDS patients at the time of clinical progression, but very few studies have determined whether these mutations are already present on clinical diagnosis. A high FLT3 expression is caused by both these as well as by other still undefined mutations. Therefore, we have decided to analyse the expression of the FLT3 gene by RT-PCR on clinical diagnosis and during disease outcome in twenty-six MDS patients. Our study was aimed at determining whether a high FLT3 expression was correlated with any peculiar clinico-haematological parameter, clinical evolution to AML and response to treatment.Fourteen patients were males and twelve females; their median age was 60 years (range 36–76). According to FAB classification seven patients were classified as refractory anemia with ringed sideroblasts (RARS), fourteen as RA and five as refractory anemia with excess of blasts (RAEB). Conventional cytogenetic studies discovered a normal karyotype in twenty patients, a del(20q) in three, a del(5q) in two and a del(12p) in one. Blast cell percentage was 0–5% in twenty patients, 6–10% in four and 11–20% in two. According to IPSS fifteen patients were considered low-risk, eight intermediate-1 risk and three as intermediate-2 risk. FLT3 expression was evaluated through a relative real-time quantification approach which used SybrGreen I as DNA binding fluorescent dye. Total RNA from mononuclear cells from a patient, who harboured an ITD of the FLT3 gene and presented a high expression of the gene, was serially diluted in order to obtain a standard curve for real-time quantification. FLT3 expression was determined by the ΔΔCt method. FLT3 levels were normalized to ABL and calibrated on a normal sample. At the onset of the disease twenty-three patients showed a FLT3 expression similar to that of the normal control, while three (one RA and two RAEB) presented a two-four fold increase. In these last patients no correlation with any particular clinico-haematological feature was noted. Nine of the twenty-six patients progressed in AML after a median time of thirty-one months (range 8–86). Three of them had already presented an increased FLT3 expression on clinical diagnosis. Considering the remaining six patients, a three-seventeen fold increase of FLT3 expression was observed in two patients and a normal FLT3 expression in the other four. Time from MDS to AML evolution was 8,22,29,33,39 months for patients with a high FLT3 expression and 31,40,42 and 86 months for those with a normal FLT3 expression. Three of the five patients with a high FLT3 expression were given different courses of intensive chemotherapy. One of them, who never responded to chemotherapy, maintained a constantly high FLT3 expression, the other two, who achieved complete remission, showed a normalization of FLT3 expression. However both of these two responsive patients again presented a six-eight fold increase of FLT3 expression on relapse.In conclusion, a high FLT3 expression i) may be observed on clinical diagnosis in about 11,5% of MDS patients, ii) does not associate with any peculiar clinico-haematological finding, iii) frequently appears at the time of AML evolution since it was detected in two of our six patients who showed a normal FLT3 expression on clinical diagnosis but a high expression on relapse.

A teenager's experience of cancer

A teenager's experience of cancer

Up-front melphalan in Ewing's family tumors with bone/bone marrow metastases at onset (very-high risk EFTs). A report from ISG/AIEOP “Very High Risk EFTs Cooperative Study”

9037 Background:Patients with very-high risk EFTs have a poor prognosis. Melphalan (L-PAM) has been widely used in myeloablative regimens in EFTs, without a prior demonstration of its effectiveness in this disease. Methods: From March 2001, a study was opened for very-high risk EFTs with the main aim to investigate the activity and toxicity of up-front L-PAM at non myeloablative doses. Treatment consisted of initial window-therapy with L-PAM (50 mg/m2 every 21 days × 2 courses) followed by 8 intensive chemotherapy courses, and consolidation with megatherapy+autologous PBSC rescue. PBSC collection was scheduled in responders after the 4th/6th chemotherapy course. Surgery and radiotherapy were employed on individual basis Results: As of September 2003, 17 consecutive patients (median age 16yrs, range 9–34) were enrolled. All patients were evaluable for toxicity and up-front L-PAM activity. No severe toxicities were reported, but for grade 3–4 hemopoietic toxicity. After L-PAM courses, grade 4 neutropenia, thrombocytopenia, anemia were registered in 76%, 68%, and 41% of cases, respectively. Responses after the up-front phase according to the RECIST criteria were as follows: 13/17 (76%) PR, 2/17 (12%) SD, 2/17 (12%) PD. Up to date 13 patients were evaluable for PBSC collection. Ten/13 (77%) mobilized PBSC adequately, and the median harvest was 5 × 106 CD34+/kg (range 2.6 –15 × 106). Conclusions: L-PAM proved to be active. Toxicity was predictable and manageable. Moreover, the scheduled L-PAM doses allowed PBSC collection even after further intensive chemotherapy in most cases. No significant financial relationships to disclose.

Acute neurotoxicity in children with advanced stage B-non-Hodgkin's lymphoma and B-acute lymphoblastic leukaemia treated with the United Kingdom children cancer study group 9002/9003 protocols

We reviewed the pattern of acute neurotoxicity in children with B-non-Hodgkin's lymphoma (B-NHL) and B-acute lymphoblastic leukaemia (ALL) treated with the UKCCSG 9002/9003 protocols. Among 175 patients, 21 (12%) developed acute neurotoxicity: 9002 protocol ( n=11/112) and 9003 ( n=10/63). There were 20 boys and the median age was 10 years. Patients with neurological symptoms due to other causes were excluded. Acute neurological symptoms developed following induction chemotherapy in 7 patients, or after a more intensive course of chemotherapy containing high-dose methotrexate ( n=14). Nine patients required their chemotherapy to be altered because of the acute neurotoxicity. One patient died of cerebral haemorrhage but none of the remaining six deaths was attributed to acute neurotoxicity. We conclude that acute neurotoxicity is common in children treated with the 9002/9003 protocols and tends to be transient. Intrathecal and systemic chemotherapy including high-dose methotrexate is probably the most common predisposing factor. Modification of subsequent chemotherapy is not invariably necessary.

Occult tumor cell contamination in patients with stage II/III breast cancer receiving sequential high-dose chemotherapy

The purpose of this study was to evaluate the presence of micrometastatic cells in the apheresis products from patients with breast cancer, and also to determine if repeated infusion of contaminated products had any clinical impact. A total of 94 patients with high-risk breast cancer were enrolled in a prospective single center study to evaluate the use of dose-intensified chemotherapy (doxorubicine 75 mg/m(2) and cyclophosphamide 3000 or 6000 mg/m(2) for four cycles) with repeated (x 2) stem cell reinfusion. All women were monitored for the presence of metastatic cells in aphereses, collected after first course of intensive chemotherapy, and following additional mobilization with rhG-CSF. Epithelial cells were screened with monoclonal antibodies directed to cytokeratin. Eight of the 94 patients had detectable tumor cells in one or several aphereses collected after intensive chemotherapy; this was unrelated to other tumor characteristics, including size, histology, Scarff Bloom and Richardson (SBR) grading (presence or absence of hormone receptors). Hemato-poietic reconstitution was similar in the cells from these eight patients, and in the total patient population. Three of these eight patients relapsed. This study has confirmed that contamination of apheresis products remains a rare event, which does not seem to affect clinical evolution, even when reinfused into the patient.

Salvage therapy in refractory acute myeloid leukemia: prediction of outcome based on analysis of prognostic factors

Acute myeloid leukemia (AML) non-responsive to initial chemotherapy is generally of poor prognosis. High-dose cytarabine (HD-AraC) has been proposed as salvage therapy in combination with amsacrine. The aim of the current study was first to assess the toxicity and the efficacy of such a combination therapy, and secondly to determine prognostic factors allowing to predict whom patients could benefit of such a treatment. Out of 91, 45 patients referred to our institution have been treated by HD-AraC (3 g/m 2/12 h from day 1 to 4) combined with amsacrine (90 mg/m 2 per day from day 5 to 7) as a salvage regimen. Forty-five of the 91 patients (49%, 95% confidence interval (CI): 39–60%) achieved complete remission (CR). Thirty-five patients were refractory to the salvage therapy and 11 patients died from toxicity during aplasia. Median disease-free survival (DFS) was 11.5 months (95% CI: 6–16 months). After CR achievement, 26 patients received consolidation therapy according to the protocol in which they were included. Nineteen patients with an HLA-identical sibling donor underwent allogeneic bone marrow transplantation. At time of analysis, 27 of the 45 patients (60%) who achieved CR have relapsed. Median overall survival (OS) was 7.5 months (95% CI: 6–15 months). There was 12 long survivors (13%). In univariate analysis, initial karyotype was the main prognostic factor as well as in terms of CR achievement ( P=0.002) than in terms of DFS ( P=0.01) or OS ( P=0.009). CR achievement was negatively influenced by higher WHO performance status index ( P=0.006), higher LDH level ( P=0.02), and higher CD34 expression by leukemic cells ( P=0.03) at diagnosis, and presence of circulating blasts ( P=0.001), platelet count <80×10 9/l ( P=0.0001), and polymorphonuclear (PMN) percentage <30% ( P=0.01) at time of starting salvage therapy. DFS was negatively influenced by secondary AML ( P=0.01), weight loss ≥5% ( P=0.03), and higher white blood cell (WBC) count ( P=0.03) at time of diagnosis. Age over 60 years ( P=0.002), prior history of toxic exposure ( P=0.01), higher CD34 expression ( P=0.02), weight loss ≥5% ( P=0.006), and WHO performance status index ≥2 ( P=0.01) at diagnosis, and platelet count <80×10 9/l ( P=0.02) at time of salvage therapy were the main prognostic factors associated with shorter OS. In multivariate analysis, karyotype grouping at diagnosis ( P=0.006) and blood count before salvage therapy ( P=0.001) were of prognostic value for CR achievement. Karyotype remained of prognostic value for DFS and OS ( P=0.007 and <0.0001, respectively). We conclude that HD-AraC combined with amsacrine was as a useful salvage regimen in AML non-responding to a first intensive course of chemotherapy. Using objective parameters of proven significance (karyotypic grouping and blood count before salvage), we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with favorable risk cytogenetics and those with intermediate risk cytogenetics and favorable blood count (PMN ≥30%, no circulating blasts, and platelet count ≥80×10 9/l) before salvage therapy had a similar outcome than those achieving CR after only one course of chemotherapy. All other patients displayed a poor outcome. This suggests their orientation at an earlier time to alternate therapeutic programs based on investigational drugs.

Current Controversies: Which Patients With Acute Myeloid Leukaemia Should Receive A Bone Marrow Transplantation? – An Adult Treater's View

Current Controversies: Which Patients With Acute Myeloid Leukaemia Should Receive A Bone Marrow Transplantation? – An Adult Treater's View

Disappearance of AML1-MTG8 transcript by reverse transcriptase polymerase chain reaction in a patient in remission of acute myeloid leukemia (M2) after low-dose cytosine arabinoside

It is well-known that low dose cytosine arabinoside (LDAC) has activity in elderly patients with acute myeloid leukemia (AML). Several studies have shown that AML patients with t(8;21) in long term complete remission (CR) following intensive chemotherapy or allogeneic bone marrow transplantation (BMT) still have persistence of AML1-MTG8 transcripts by reverse transcriptase polymerase chain reaction (RT-PCR) method. We report here a patient who has no evidence of residual disease detectable by RT-PCR after LDAC. A 69-year-old patient did not obtain CR after two courses of intensive chemotherapy with behenoyl-ara-C, daunorubicin, 6-mercaptopurine and prednisolone. He received subcutaneous LDAC 10 mg every 12 h and granulocyte colony-stimulating factor (G-CSF) for 29 days and achieved CR. He continued on a 21 to 28-day course of LDAC without G-CSF every 2 or 3 months and has remained well and in CR for 5 years without chimeric AML1-MTG8 transcript by RT-PCR. LDAC therapy seems to be effective in eradicating the leukemic clone as post-induction or maintenance therapy in this patient. This is the first case report of the disappearance of AML1-MTG8 transcript by RT-PCR in a patient with t(8;21) in long-term remission after LDAC.

Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial

Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse. 381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2). The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.

Disappearance of AML1 ‐MTG8(ETO) fusion transcript in acute myeloid leukaemia patients with t(8;21) in long‐term remission

In a study of 23 patients with t(8;21)-associated acute myeloid leukaemia the AML1-MTG8 fusion transcript was present in the majority of serial samples obtained from 17 patients followed for up to 34 months after diagnosis, but was absent in samples from all six patients who had been in continuous complete remission for 61 months after allogeneic bone marrow transplantation (BMT), or for 52, 53, 123, 182 and 198 months, respectively, after courses of intensive chemotherapy. Previous studies showed that the AML1-MTG8 fusion transcript was present in most patients with this type of translocation in long-term remission. Our results indicate that blood cells of patients with t(8;21) in remission of over 10 years may not show the AML1-MTG8 fusion transcript, and that those of patients who have undergone allogeneic BMT or intensive chemotherapy may become fusion transcript-negative much earlier. Our study suggests that leukaemic cells with the AML1-MTG8 fusion transcript may survive for some time after courses of chemotherapy or BMT, but that they may eventually be eradicated by immunologic and other antileukaemic mechanisms.