Cycles Of Ara-C Research Articles

Two-drug versus three-drug induction chemotherapy in pediatric acute myeloid leukemia: a randomized controlled trial

The benefit of three-drug induction chemotherapy over a two-drug induction has not been evaluated in pediatric acute myeloid leukemia (AML). We, therefore, conducted a randomized controlled trial to ascertain the benefit of a three-drug induction regimen. Patients aged 1–18 years with newly diagnosed AML were randomized to two cycles of induction chemotherapy with daunorubicin and ara-C (DA) or two cycles of ara-C, daunorubicin, and etoposide (ADE). After induction, patients in both arms received consolidation with two cycles of high-dose ara-C. The study’s primary objective was to compare the event-free survival (EFS) between the two arms. The secondary objectives included comparing the composite complete remission (cCR) rates, overall survival (OS), and toxicities. The study randomized 149 patients, 77 in the DA and 72 in the ADE arm. The median age was 8.7 years, and 92 (62%) patients were males. The median follow-up was 50.9 months. The cCR rate in the DA and ADE arm were 82% and 79% (p = 0.68) after the second induction. There were 13 (17%) induction deaths in the DA arm and 12 (17%) in the ADE arm (p = 0.97). The 5-year EFS in the DA and ADE arm was 34.4% and 34.5%, respectively (p = 0.66). The 5-year OS in the DA and ADE arms was 41.4% and 42.09%, respectively (p = 0.74). There were no significant differences in toxicities between the regimens. There was no statistically significant difference in EFS, OS, CR, or toxicity between ADE and DA regimens in pediatric AML. The trial was registered with the Clinical Trial Registry of India (Reference number: CTRI/2014/11/005202).

Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: Results of CALGB 51101 (Alliance).

7506 Background: Optimal consolidative therapy for primary central nervous system lymphoma (PCNSL) is not defined. Avoidance of whole brain radiation may reduce risk of neurotoxicity. Non-radiation consolidative options include myeloablative chemotherapy with autologous stem cell transplantation (HDT/ASCT) or non-myeloablative chemotherapy. Methods: This is a randomized phase 2, National Clinical Trials Network study of induction methotrexate (MTX) (8 g/m2 days 1, 15), temozolomide (TMZ) (150-200 mg/m2 D7-11), and rituximab (RTX) (C1 D3, 10, 17, 24 and C2 D3, 10 ) in four 28-day cycles followed by one cycle of cytarabine (ARA-C) (2 g/m2 BID, D1, 2) (MTRA). After induction, patients (pts) received consolidation with thiotepa (5 mg/kg BID, D -5, -4) plus carmustine (400 mg/m2, day -6) and ASCT (Arm A) or one cycle of ARA-C (2 g/m2 BID, D1-4) plus infusional etoposide (40 mg/kg over 96h) (Arm B). Pts were stratified on age and performance status and randomized 1:1 before induction. The primary endpoint was progression-free survival (PFS) from randomization. With 110 pts, there was 84% power to detect an improvement in PFS using a log-rank test (1-sided α= 10%), assuming a median PFS of 3 months for pts who progress during induction, and a median PFS of 2 years (yrs) for Arm B and 4.5 yrs for Arm A consolidation. This report includes the results for the primary endpoint analysis. Results: 113 pts (median age 61 yrs, range 33-75) were randomized (Arm A: 57, Arm B: 56) across 27 centers. 108 eligible pts who received induction therapy were included in the primary endpoint analysis (Arm A: 54, Arm B: 54). 72/108 pts started consolidation and 70/72 completed consolidation per protocol (Arm A: 36, Arm B: 34). With a median follow-up of 3.8 years, median PFS from randomization was 6 yrs (95% CI 3.9-not reached) in Arm A vs 2.4 yrs (95% CI 0.6-not reached) in Arm B (p = 0.02). However, more pts randomized to Arm B went off treatment before consolidation due to progression or death (28% vs 11%, p = 0.05). PFS landmarked at start of consolidation demonstrated a trend for improved PFS favoring Arm A (HR 0.58, 95% CI 0.25-1.36; p = 0.21). Median OS was not reached in either arm, and 3-yr estimates were 83% (95% CI 69-91; Arm A) vs 72% (95% CI 57-82; Arm B). Toxicities were similar between arms with no treatment-related mortality during consolidation. Conclusions: MTRA induction followed by myeloablative consolidation (Arm A) had improved PFS vs MTRA induction followed by non-myeloablative consolidation (Arm B), though more progressions or deaths leading to treatment discontinuation prior to consolidation in Arm B were noted. Both consolidation regimens were well-tolerated with encouraging PFS and OS in newly-diagnosed PCNSL. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01511562.

Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: Results of induction therapy in Alliance 51101.

8042 Background: Optimal consolidative therapy for primary central nervous system lymphoma (PCNSL) is not defined. Avoidance of whole brain radiation may reduce risk of neurotoxicity. Non-radiation consolidative options include myeloablative chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) or non-myeloablative chemotherapy. Methods: This is a randomized phase 2, National Clinical Trials Network study of induction methotrexate (MTX) (8 g/m2days 1, 15), temozolomide (TMZ) (150-200 mg/m2 D7-11), and rituximab (RTX) (C1 D3, 10, 17, 24 and C2 D3, 10) in four 28-day cycles followed by one cycle of cytarabine (ARA-C) (2 g/m2 BID, D1, 2) (MTRA). Following induction, patients (pts) received consolidation with thiotepa (5 mg/kg BID, D -5, -4) plus carmustine (400 mg/m2, day -6) and ASCT (Arm A) or one cycle of ARA-C (2 g/m2 BID, D1-4) plus infusional etoposide (40 mg/kg over 96h) (Arm B). The primary endpoint was median progression-free survival (PFS), designed to compare consolidation regimens. This report describes the results of the 5 cycles of induction therapy. Results: 113 pts (median age 61 years, range 33-75) were randomized (Arm A: 57, Arm B: 56) across 27 centers. 108 eligible pts who received induction therapy were evaluated. 36 pts (33.3%) did not proceed to consolidation, mainly due to disease progression (17), pt withdrawal (8), or adverse events including death (6). Grade 3 or 4 febrile neutropenia occurred in 12 pts (11.1%) during induction. Dose modifications of MTX were required in 75% of pts and 63.3% of cycles, mainly due to renal adjustments. Dose delays of MTX were required in 52.8% of pts and 22.2% of cycles. Overall response rate (CR, CRu, PR) at the end of induction was 65.7% (95% CI, 56%, 74.6%). Conclusions: While MTRA is feasible and active a significant proportion of pts did not receive consolidation, supporting the need to develop more effective induction strategies. Clinical trial information: NCT01511562 .

Treatment of Elderly and Unfit AML Patients with Prolonged Administration of Low Dose Cytarabine and Thioguanine Achieves High Complete Remission Rates in an Outpatient Setting

Background: The treatment of elderly or unfit patients with AML is disappointing with little improvement in the past 30 years. Studies in the 1960s (Clarkson, Cancer 1972) explored the use of prolonged low dose cytarabine (Ara-C) with frequent bone marrow monitoring until marrow hypoplasia. Treatment was given as long as needed with up to 6 weeks continuous therapy with some studies combining with synergistic thioguanine (TG). We developed a modification of the prolonged therapy concept using a 21 day course of low dose subcutaneous Ara-C with TG. Maintenance therapy with the same drugs was given for 2 yrs.Aim: To assess the safety and efficacy of low-dose sc cytarabine in combination with TG in patients with AML.Methods: Patients included (i) de novo AML, aged > 65, or unfit for intensive chemotherapy or (ii) patients >18 yrs with relapsed/refractory (R/R) AML. Patients received repeated administration of cycles of Ara-C 20mg/m2 s/c once daily with TG 40 mg/m2 PO once daily for 21 days. Bone marrow biopsy was performed within 4-7 days of completing the 21-day cycle and if blasts > 5% the next cycle was started immediately.There was no specified limit to the induction cycles which was at the investigators discretion considering patient tolerability. Once remission was achieved cycles were reduced to 14 days every 4-6 weeks for 2 years. Supportive care mandated posaconazole, ciprofloxacin, amoxycillin and pegfilgrastim 6 mg every 14 days continued until remission. Treatment was administered in an outpatient setting and Ara-C was given in the home by community nurses or local medical practitioners. The study was approved by the local hospital Human Ethics Committee and registered on the ANZ Clinical Trials Registry (ACTRN12617000231347).Results: Sixty patients were treated, Median age was 75 (range 72-94), 42 (70%) had de-novo AML and 18 (30%) R/R AML. Presenting WCC ranged from 0.8 to 185. Adverse cytogenetics were present in 40 (66%). In de-novo patients, 17 (40%) had prior haematologic disorders and 4 (10%) were treatment related. Response rates were: complete remission 40% or CR with incomplete count recovery (CRi) 28.5% in the entire cohort giving a response rate of CR+CRi of 68.5%. In the newly diagnosed group CR/CRi was 74%. Responses were also seen in the relapsed/refractory group with 5 of 18 (30%) achieving CR/CRi. The median number of cycles to achieve remission was 2 but some patients required up to 4 cycles. There were 9 (15%) deaths during induction. The median overall survival is 15 months in the de-novo group and 5 months in the relapsed/refractory group. A proportion of patients, 20-25% remain alive and in remission at 3 years post treatment. The main toxicity was as expected in this group of patients with infections predominating. No cases of severe liver toxicity were seen despite the prolonged use of thioguanine.Conclusion: Prolonged therapy with low dose Ara-C and TG can be given as an outpatient in elderly AML patients. Complete remission rates appear equal to or better than other commonly used protocols. Anthracyclines are not used. Toxicity was manageable and mainly neutropenia related but some patients never developed serious infections or required hospitalisation. We suggest that this concept of prolonged low dose cytotoxics with individual patient adjusted therapy based on bone marrow response has been overlooked since it was first proposed 40-50 years ago. Further studies are required to independently confirm these results. DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia

Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia

Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS).Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation.Results. Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%).Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2).The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group.With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively.Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. [Display omitted] [Display omitted] DisclosuresDoorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?

Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?

Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) comprises approximately 5 % of all primary brain tumors. During the past two decades the incidence of PCNSL has increased, and as a result clinical research to determine the optimal treatment for PCNSL patients also has increased. Diagnosis is based on histopathologic findings traditionally established by biopsy only. More recent data raise controversy and challenges this biopsy-only paradigm, showing a potential advantage for surgical resection with progression-free survival (PFS) and overall survival (OS). Using high-dose intravenous (IV) methotrexate-based chemotherapy alone or as part of a regimen can lead to disease cure. The role of whole brain radiotherapy (WBRT) remains controversial and more frequently is omitted to avoid potential delayed neurocognitive effects, especially in patients older than age 60 years. Newer data from Memorial Sloan Kettering Cancer Center (MSKCC) using five cycles of Rituximab, Methotrexate, Vincristine, and Procarbazine (R-MVP) followed by low-dose WBRT (2,340 cgy), and then two cycles of Ara-C had excellent disease control with low neuro-toxicity and is now the basis of an ongoing RTOG (Radiation Treatment Oncology Group) trial comparing early versus delayed WBRT. Other chemotherapeutics and novel treatments, such as autologous stem cell transplantation, are being studied for potential use in PCNSL. Unlike many other primary brain tumors seen in adults, PCNSL is potentially curable; therefore, balancing treatment decisions with long-term neurocognitive effects and toxicities is crucial.

Combination immunochemotherapy followed by reduced dose (rd) whole brain radiation therapy (WBRT) in an expanded cohort of patients with newly diagnosed primary central nervous system lymphoma (PCNSL)

2072 Background: High-dose methotrexate (M)-based chemotherapy combined with WBRT has improved survival in patients with PCNSL. However, disease recurrence and treatment-related neurotoxicity are significant problems. We conducted a prospective trial incorporating rituximab (R) and rdWBRT and previously demonstrated this was feasible. This study was extended to assess the long-term outcome of this approach in an expanded cohort. Methods: Patients were treated with R-MPV (d1 R 500mg/m2; d2 M 3.5gm/m2; vincristine 1.4mg/m2; d1–7 procarbazine 100 mg/m2/d on odd-cycles). Patients with a PR after five cycles received two additional cycles. Patients with a CR received rdWBRT (2340cGy), otherwise patients received standard WBRT (4500cGy). Patients then received two cycles of Ara-C 3gm/m2. Prospective neuropsychological evaluations were performed at baseline, before WBRT, and every 6 months thereafter. Results: From October 2002 to September 2008, 50 patients were enrolled (22 female, 28 male), median age 59.5 years (range 30–79 years). Due to neutropenia in two of the first five patients, all subsequent patients received G-CSF. 42 patients are assessable for response (4 patients died from progressive disease prior to completing the first cycle of treatment, 4 patients - treatment ongoing). 33 patients (79%) had a CR, of whom 29 received rdWBRT (3 refused, 1 died). At median follow-up of 3 years for survivors the median OS has not been reached and the estimated 2-year OS is 68%. Patients treated with rdWBRT have a median follow up of 38 months: 21 (72%) are alive with no evidence of disease, seven (24%) relapsed, and one died of unknown causes. Eight of 21 (38%) who are alive with no evidence of disease were age 60+ at diagnosis. The number of patients treated with rdWBRT alive with no evidence of disease at 3, 4, and 5 years is 12, 8, and 4 respectively. 9 patients have completed neuropsychological evaluations 24 months after rdWBRT with no significant cognitive decline detectable. Conclusions: Prolonged follow-up of an expanded cohort of patients treated with immunochemotherapy followed by rdWBRT for patients with an initial CR continues to support our initial conclusions that this approach results in excellent disease control with no observed treatment-related neurotoxicity. [Table: see text]

Hematological Improvement in AML/RAEB Elderly Patients Treated with Valproic Acid and Low-Dose ARA-C

Histone deacetilase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects. Valproic acid (VPA) has HDCAi activity and synergizes with Ara-C to differentiate AML blasts in vitro. VPA is orally applicable and has a low toxicity prophile. We tried to assess the therapeutic activity of VPA in combination with low-dose Ara-C in elderly/frail AML/RAEB patients. We enrolled in this study 31 patients with Myeloid Pathologies. Fifteen pts had diagnosis of oligoblastic AML (M0:2, M1: 7, M2: 1, M4:1, M5: 4); 13 patients had RAEB (RAEB 1: 2, RAEB 2: 11) with the following IPSS: int-1=2, int-2= 2, high= 6. Three other patients had progression from previous MPS (1 from ET, 2 from LMMC). Median age was 70 yrs (range: 53 to 84). Median time from Diagnosis to treatment was 15 months (range 1 to 79). Clinical status at start of protocol was: at Diagnosis = 13 pts, Resistant after induction =6 pts, Relapsed after CR =11 pts, Relapsed after allogeneic transplant =1 pt). All patients were excluded from conventional chemotherapy for age and multiple comorbidities. In 27 out of 31, these comorbidities required therapy or periodic controls (grade 3), other 2 pts had one of G4 grade (life-threatening). Thirteen patients were defined “frail” because they presented 3 of G3 comorbidities or at least a G4 one. Twenty-nine pts were evaluated for autosufficiency with ADL score, 5 of them didn't reach the score of 6, showing impairment in their autosufficiency. Assessing functional autonomy, IADL score showed deficiency in 17 of 29 patients. In our protocol, VPA was administered in continuum to reach serum concentration of 50–100μg/ml. Ara-C was given in cycles of 8 days, 40 mg/day. Ammonium and valproic acid serum level was routinely checked. Bone marrow examination was done at the enrollement in the study, after sixth cycle of Ara-C and/or if improvement of blood counts were observed. In two patients that were in CR at the end of sixth cycle, VPA was maintained; other six cycles of Ara-C were given monthly and thereafter every third month until relapse. Six patients received the treatment for at least 6 cycles, the other patients had a median of 2 cycles, (range 1 to 4). Ten patients are still in treatment, 17 dropped out for progression/death, one patient underwent reduced intensity allotransplant while in remission. From the start of protocol, median overall survival was 4 mths, range 1 to 33 mths. Fifteen pts are alive now. Overall, 11 of 31 patients (35%) had hematological improvement (according to IWG, 2008), including 7 CR (22%) with clearing of blasts in the marrow and normalization of blood counts. The median cycle of improvement was 2 (range 1 to 4) and the median duration of improvement was 2 months (range 1 to 23 months), including two pts that lasted in CR for 10 and 23 months; 3 pts are still in CR at 5,8 and 10 mths from the starting of response, one patient is in Hematological Improvenment at 2 mths. Hematological toxicity requiring platelet transfusion was seen in 17 patients, while 10 pts required red cell transfusion. Transient hyperammoniemia was seen in one patient; liver toxicity in another patient. Neutropenia-related infections were seen in 3 pts. Adding VPA to low-dose Ara-C, some complete responses and some improvements in peripheral cytopenias can be achieved without a significant increase in toxicity. Therefore this therapeutic protocol is feasible for elderly/frail oligoblastic AML/RAEB patients who cannot have aggressive therapy.

High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Primary CNS Lymphoma: Updated Results from a Pilot and Phase II Study

Introduction: High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in younger patients (pts.). A 5-year overall survival probability (OS) of 69% could be demonstrated in 30 pts within a phase-II trial on HDT and ASCT with consolidating whole-brain-irradiation (WBRT) (Illerhaus et al. JCO 2006). A subsequent pilot trial on HDT and ASCT without WBRT showed a 5-year OS of 77% (Illerhaus et al. Haematologica 2008). Here we give an update of our two different treatment regimens and future perspectives.Patients and Methods: Thirty pts. ≤65 years were treated within the phase II trial, chemotherapy (CHT) consisted of 3 cycles of high-dose methotrexate (MTX, 8 g/m2), 1 cycle of AraC (2× 3 g/m2) plus thiotepa (TT, 40 mg/m2) followed by rG-CSF and stem-cell-mobilization. Conditioning regimen included BCNU (400 mg/m2) and TT (2×5 mg/kgBW) followed by ASCT. Hyperfractionated WBRT (45 Gy, 2×1Gy/d) was administered as consolidation. In our subsequent pilot trial 13 pts. (age 38–67 years) were treated without consolidating WBRT; CHT was intensified with 4 cycles MTX 8g/m2, 2 cycles AraC (2× 3 g/m2) and TT (40 mg/m2). Dose escalated HDT included BCNU (400 mg/m2) and TT (4×5 mg/kgBW) followed by ASCT. WBRT was reserved for pts. not responding to CHT.Results: Median follow-up of the 30 pts. treated within our phase II trial was extended to 95 months (mo), the updated 5-year OS of all pts. is 66.6% and 82,3% of the subgroup of pts. who underwent HDT and ASCT (n=23), respectively. Three additional deaths occurred due to relapse (n=2) after 45 and 71 mo and due to comorbidity (n=1) after 103 mo. Five of 30 pts. developed severe leukoencephalopathy during follow-up. With a median follow-up of 35 mo in the 13 pts. treated within the pilot-phase without consolidating WBRT 3-year OS of all pts. is 77%. No further relapse or non-relapse mortality occurred in this pilot-group during. Most recent follow-up data will be presented in detail.Conclusion: Sequential systemic application of high-dose cytostatic agents followed by HDT+ASCT is highly effective as initial therapy for pts. with PCNSL. The restriction of WBRT to refractory disease shows similar OS rates and a decrease in neurotoxicity. In an ongoing multicenter phase-II trial immunotherapy with rituximab is combined with HDT and ASCT to further increase remission rates. A future randomized trial should be focused on the efficacy of consolidation with HDT supported by ASCT.

Significance of persistent Auer rods and cytogenetic abnormality after first cycle of therapy for acute promyelocytic leukaemia

A 30-year-old man was diagnosed as having acute promyelocytic leukaemia (APL) with hypergranular promyelocytes, Auer rods and faggot cells (upper left). The diagnosis was confirmed by the presence of t(15:17)(q22:q21) and PMLRARA gene fusion as detected by fluorescence in situ hybridisation (FISH, upper right). Treatment with all-trans retinoic acid (ATRA) plus cytosine arabinoside (Ara-C) and daunorubicin (DNR) resulted in rapid clearance of leukaemic cells from blood. Bone marrow examination on day 27 posttherapy showed a hypercellular marrow and many maturing granulocytes containing Auer rods (lower left), but no hypergranular promyelocytes or faggot cells or increase in blasts. Thirteen per cent of the nuclei were positive for PMLRARA by FISH (lower right). He continued to receive ATRA (until day 60) and started another cycle of Ara-C and DNR on day 49 as per protocol. A repeat bone marrow on day 72 showed complete absence of both Auer rods and the PMLRARA translocation. Auer rods are the hallmark of acute myeloid leukaemia. Their presence in a post-therapy specimen is diagnostic of persistent or recurrent disease. The only exception is the APL subtype, where they may persist after ATRA therapy. ATRA induces differentiation of leukaemic cells without loss of morphological features including Auer rods, bilobed nuclei, absence of secondary granules or t(15:17). The Auer rodcontaining cells can be differentiated from leukaemic promyelocytes by their more differentiated appearance. Both the Auer rods and genetic abnormalities disappear with time. Thus, a change to the planned treatment protocol is not required.

Perspectivas para a leucemia mielóide aguda na infância após a observação de um grupo de pacientes tratados convencionalmente

Modern treatment of acute myeloid leukemias follows well defined guidelines: precise clinical and biological characterization, adequate aggressive chemotherapy, intensive supportive care and eventual early indication of bone marrow transplantation. In this report we present the best results obtained with conventional chemotherapy delivered to a group of pediatric patients between 1986 and 1996 and discuss the strategies for contemporary and more efficient regimens. Forty-three patients with de novo acute myeloid leukemias with ages between 6 months and 14.5 years, were treated with a 4-drug induction and consolidation program: AUNO, ARA-C, VCR and DEXA, followed by 60 weeks of maintenance with sequential cycles of ARAC & ASP, CICLO & ETO, DAUNO (6-TG) & ARA-C & VCR & DEXA and 6-TG & ARA-C & VCR & DEXA. CNS prophylaxis with intrathecal ARA-C was undertaken. No child underwent bone marrow transplantation in first remission. A total of 38/43 (84%) children achieved complete remission and event-free survival at 3 years was estimated at 24 ± 7%. The importance of discriminating AML in risk groups with particular attention paid to cytogenetic criteria and new modalities of treatment are discussed. The current relevance of bone marrow transplantations is emphasized.

Daunorubicin and Cytarabine Compared with Daunorubicin, Cytarabine and the MDR1 Reversal Agent PSC-833 in Elderly Patients with Acute Myelogenous Leukemia.

Older patients (pts) have a high incidence of P-glycoprotein (P-gp) positive AML blast cells. P-gp acts as drug efflux pump for a variety of agents including daunorubicin (DNR). The P-gp inhibitor PSC-833 can inhibit the function of P-gp in AML cells and restore sensitivity to DNR. Combining PSC-833 with DNR may improve response rate and survival in AML pts. However, previous intervention studies have produced conflicting results. From 1997 to 1999 we conducted a multi-center phase 3 study in pts of older age with previously untreated AML, in which we prospectively investigated the effect of PSC-833 combined with standard antileukemic treatment in relation to the flowcytometric P-gp status at diagnosis. Pts were randomized to receive two cycles of DNR (45 mg/m2, days 1-3) and Ara-C (200 mg/m2, 7 days) or the same regimen with a lower dose of DNR (35 mg/m2, days 1–3) plus PSC-833 (2 mg/kg loading dose followed by 10 mg/kg/24h for 72 hours). Pts who attained a complete remission (CR) were to receive a common consolidation cycle of Ara-C (1 g/m2, days 1–4), mitoxantrone (6 mg/m2, days 1–4) and etoposide (80 mg/m2, days 1–4).Results. 428 pts were randomized (214 in each arm) with 419 eligible and evaluable. Median age was 67 years (range 58–85). Baseline characteristics were comparable between the two arms. Cytogenetics was successfully performed in 293 pts; 5 had favorable and 66 had unfavorable abnormalities. P-gp expression was assessed in fresh, purified bone marrow samples of 309/419 pts (74%) by determining the Rhodamin123 efflux ratio with/without PSC-833 in vitro and by assessment of the UIC2 and MRK16 expression ratios. Upon P-gp assessment combining the 3 tests, pts were classified as P-gp negative (27%), low positive (29%), positive (28%) or highly positive (17%). Median follow up is 56 months. CR and 5-year survival rates with 95% confidence intervals are in the table below. Increased P-gp expression was associated with a lower CR rate (P=0.02), worse event-free survival (EFS) and overall survival (OS), P=0.01. There was also no significant effect of PSC-833 on the CR rate, OS, EFS or disease-free survival (DFS) when P-gp status was included in a multivariate analysis. In the planned subgroup analysis of pts with P-gp expression, who were expected to benefit most from PSC-833, CR rate was somewhat higher in the PSC arm (61% vs. 51%, P=0.07), however, OS, EFS and DFS were not different (P=0.8, 0.9 and 0.15). Analysis of frequently occurring polymorphisms of P-gp in exons 12, 21 and 26 revealed that pts who had wildtype genotype alleles in all 3 exons had a relatively poor survival as compared with those with heterozygous or homozygous mutant alleles in all 3 exons.Conclusions. Addition of PSC-833 to DNR and Ara-C does not improve CR rate nor long-term OS, EFS and DFS in elderly AML pts. P-gp expression remains an independent adverse prognostic factor in AML pts treated with P-gp reversal.Results by treatment armcontrol (n=211)PSC-833 (n=208)P-valueCR48% (41–55)54% (47–61)0.22EFS8% (5–13)7% (4–11)0.46DFS17% (11–26)13% (8–20)0.0610% (6–15)10% (6–15)0.52

The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia--analysis of 848 patients.

We studied the impact of cytogenetics and kind of induction/consolidation therapy on 848 adult acute myeloid leukemia (AML) patients (age 15-83). The patients received three types of induction/consolidation regimen: standard (daunorubicin and cytosine arabinoside (3/7); two cycles); intensive (idarubicin, cytosine arabinoside and etoposide (ICE), plus mitoxantrone and intermediate-dose Ara-C (NOVIA)); and low-dose (low-dose cytosine arabinoside). CR patients under 60 years of age, if an HLA-identical donor was available received allogeneic stem cell transplantation (allo-SCT); otherwise, as part of the program, they underwent autologous (auto)-SCT. CR rates significantly associated with 'favorable' (inv(16), t(8;21)), 'intermediate' ('no abnormality', abn(11q23), +8, del(7q)) and 'unfavorable' (del (5q), -7, abn(3)(q21q26), t(6;9), 'complex' (more than three unrelated cytogenetic abnormalities)) karyotypes (88% vs 65% vs 36%, respectively; P = 0.0001). These trends were confirmed in all age groups. On therapeutic grounds, intensive induction did not determine significant increases of CR rates in any of the considered groups, with respect to standard induction. Low-dose induction was associated with significantly lower CR rates. Considering disease-free survival (DFS), multivariate analysis of the factors examined (including karyotype grouping) showed that only age > 60 years significantly affected outcome. However, in cases where intensive induction was adopted, 'favorable' karyotype was significantly related to longer DFS (P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction. Patients receiving allo-SCT had significantly longer DFS (P = 0.005); in particular, allo-SCT significantly improved DFS in the 'favorable' and 'intermediate' groups (P = 0.04 and P = 0.048, respectively). In conclusion our study could provide some guidelines for AML therapy: (1) patients in the 'favorable' karyotype group seem to have a longer DFS when treated with an intensive induction/consolidation regimen, adopted before auto-SCT instead of standard induction; this underlines the importance of reinforcement of chemotherapy, not necessarily based on repeated high-dose AraC cycles. Allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment; (2) patients in the 'intermediate' karyotype group should receive allo-SCT; (3) patients in the 'unfavorable' karyotype group should be treated using investigational chemotherapy, considering that even allo-SCT cannot provide a significantly longer DFS, but only a trend to a better prognosis.

Goralatide (AcSDKP), a negative growth regulator, protects the stem cell compartment during chemotherapy, enhancing the myelopoietic response to GM-CSF.

The aim of our study was to investigate the protection afforded to the bone marrow by Goralatide (AcSDKP), an inhibitor of hemopoietic stem cell proliferation, when administered alone or in combination with a growth factor (granulocyte/macrophage colony-stimulating factor [GM-CSF]) during iterative cycles of Ara-C (cytarabine) treatment. In control mice receiving the inhibitor alone without Ara-C, the number of granulocytes was reduced during treatment, and a surge in number of peripheral blood cells was observed after its completion. Peripheral hematological responses were monitored during 3 consecutive cycles of Ara-C chemotherapy and the resultant nadir and recoveries. Analysis of variance of the treatment effects pooled over the 3 cycles showed that a treatment regimen in which the inhibitor was administered during the myelotoxic periods of chemotherapy confirmed the existence of a surge after completion of administration of the inhibitor and showed a significant protective effect. When the cycles of chemotherapy plus Goralatide were followed by GM-CSF, the recovery from leukopenic nadirs was accelerated and the white blood cells and granulocyte levels were markedly increased over those observed in control mice and in mice treated either with Goralatide alone or with GM-CSF alone. The differences were highly significant. A consistent and significant increase (p < 0.001) in platelet count was also noted in animals given Goralatide in conjunction with Ara-C or Ara-C + GM-CSF. After three treatment cycles, this response to the CSF was far better in mice treated by the inhibitor than when CSF was given alone, suggesting a protection of the stem cell pool.

All Trans Retinoic Acid with Low Dose Cytosine Arabinoside in the Treatment of Myelodysplastic Syndrome

The demonstration of synergistic interaction between differentiation inducing agents and DNA synthesis inhibitors suggests that these two groups act by two different mechanisms. We prospectively studied the response rate, response duration, survival, and toxicity in 10 patients with myelodysplastic syndrome (MDS) treated with all trans retinoic acid (ATRA) and low dose cytosine arabinoside (ara-C). These patients diagnosed between October 1993 and May 1995 were treated with ATRA (45 mg/M2/day) for 90 days followed by 90 mg/M2 on alternate day till Day 275; together with Ara-C (10 mg/m2) subcutaneously twice daily for 21 days for a total of 6 cycles. These patients were analyzed for response after 3 cycles of LD Ara-C and at the time of completion of therapy. Toxicity was recorded at the end of each cycle of Ara-C. There were 6 male and 4 female patients in the age range of 24 to 76 years. The morphological diagnosis was chronic myelomonocytic leukemia in 2, refractory anemia with excess blasts in 4 and refractory anemia with excess blasts in transformation in 4. Only 1 patient achieved a complete remission and 1 patient achieved a partial response. Four patients had progressive disease on treatment. One patient died of neutropenic sepsis and 1 of resistant thrombocytopenia and intracranial hemorrhage while on treatment. One patient refused further treatment after a minor clinical response and in 1 patient treatment was stopped due to toxicity. This data in a pilot study with a limited number of patient suggests that ATRA in combination with Ara-C has little effect in MDS.

Interferon-alpha-2C and LD ara-C for the treatment of patients with CML: Results of the austrian multicenter phase II study

Small pilot studies of patients with CML have reported on encouraging response rates after treatment with interferon-alpha (IFNα) in combination with low-dose cytosine arabinoside (LD ara-C). We therefore initiated a multi-center phase II trial in order to investigate the efficacy and tolerability of this combination in newly diagnosed patients with Ph-positive chronic myelogenous leukemia (CML). Eighty-four patients were treated with IFN-α-2c at daily subcutaneous doses of 3.5 MU and LD ara-C added subcutaneously for 10 days every month at a dose of 10 mg/m 2, following an initial reduction of WBC to less than 20 × 10 9/l with hydroxyurea (HU). Within a median observation period of 28 (5–59) months the patients received a median of 7 (1–35) IFNα and LD ara-C cycles. Treatment was stopped due to side effects in 16 cases (19%) and to primary or secondary treatment failure in 38 cases (45%). In 45 patients (54%) complete hematological response (CHR) was achieved; in 39 patients (46%) cytogenetic responses including 15 (18%) complete cytogenetic responses (CHR) were observed. Median duration of cytogenetic responses was 15 months. Relapses were seen in 8 15 patients (53%) with complete cytogenetic remission (CCR), in 3 6 patients (50%) with partial cytogenetic response and in 9 18 patients (50%) with minor cytogenetic response. In conclusion, the combination of IFNα and LD ara-C resulted in encouraging rates of hematological and cytogenetic responses in patients with CML with low to moderate toxicity.

The role of timing of high-dose cytosine arabinoside intensification and of maintenance therapy in the treatment of children with acute nonlymphocytic leukemia

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.

Cisplatin and low-dose cytosine arabinoside in advanced cancer.

Twenty-two patients with advanced malignancies were treated with low-dose cytosine arabinoside (ara-C) (45 mg/m2 sc every 12 h for 3 days) and cisplatin (DDP) (100 mg/m2 ev on day 2, 2 h after ara-C. Patients received 61 cycles of ara-C + DDP with a median number per patient of 2.7 cycles (range, 1-5). All patients were evaluable for toxicity and response. Overall, 6 of 22 patients (27%) obtained an objective response (2 CR + 4 PR) with a median response duration of 20 weeks. Hematologic and gastrointestinal toxicities were moderate. Our results show a low response rate with the ara-C and DDP combination compared to the interesting results obtained in vitro.