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Abstract 4024 Background: The hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in different MDS subtypes. Compared to other response predictors to DAC, prior MDS duration has received only limited attention (1, 2), with conflicting results. Based on our finding that long duration of MDS prior to DAC treatment may be a novel factor linked to a better outcome (1), we now assess its value in the phase III trial 06011 (DAC versus BSC [3]). Immediate enrolment after diagnosis was allowed in that trial, median MDS duration prior to randomization thus only 3 months (mths). Methods: Comparison of progression-free (PFS), AML-free (AMLFS) and overall survival (OS) according to MDS duration >= vs. Results: A better prognosis of patients with MDS duration >=3 vs =3 mths (B vs D). In both arms (n=233), Mult. indicated that MDS duration (>=3 vs Conclusion: In intermediate-2 and high-risk MDS pts, long duration from MDS diagnosis to start of DAC or BSC appeared to be associated with a better outcome. This finding is in sharp contrast to the adverse prognostic impact of antecedent disease duration in patients who received intensive chemotherapy (4). It is supported by a similar analysis of pts with AML from MDS treated on the 00331 DAC phase II multicenter trial: those with longer MDS duration prior to DAC also had better outcome (5). Application of this discriminator in the evaluation also of other DAC schedules and MDS treatments therefore appears warranted. References: 1. Wijermans et al., Ann. Hematol. 84 (suppl. 1): 9–14, 2005 2. Kantarjian et al., Cancer 109:265-73, 2007 3. Wijermans et al., Blood 112 (suppl. 1): abs. 226, 2008 4. Estey et al., Blood 90:2969-77, 1997 5. Lübbert, Schmoor et al., abstract submitted, ASH 2010 Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salih:Pfizer: Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Abstract 4141 Medically non-fit AML patients (pts), often with adverse cytogenetics, have few therapeutic options. We performed a large phase II trial in untreated AML pts >60 years ineligible for induction. Primary endpoint was best response: complete (CR) or partial remission (PR) or an antileukemic effect (ALE, >25% bone marrow [BM] blast reduction). Secondary endpoints: overall survival (OS) and safety. DAC was given at 15 mg/m2 q8 hours on day 1-3, total 135 mg/m2, q6 weeks for up to 4 cycles, with ATRA (45 mg/m2/day p.o. for 28 days in cycle 2) to be administered to pts not attaining a CR or PR after course 1, i.e. those with ALE or stable disease (SD). Maintenance with 20 mg/m2 DAC i.v. over 1 hour on 3 days (total 60mg/m2, outpatient administration) q 6-8 weeks was offered to pts completing all 4 cycles. 227 pts were recruited (median age 72 yrs, range 56-86). 38% of pts were ≥75 yrs of age, 23% had a performance status of ECOG > 2, and by comorbidity scoring (HCT-CI) 80% of pts had at least one, and 36% had three or mor comorbidities. Adverse cytogenetics or preceding MDS were present in 34% and 54%, respectively. Median WBC before treatment was 4400/μl (range, 500-241 000, >50 000/μl in 10%). Median BM blasts were 55% (10-100). A median of 2 DAC cycles was given (range 1-4). 100 pts received ATRA during course 2, and 51 pts (out of 79 who completed 4 cycles) received a total of 306 DAC maintenance cycles (median 5, range 1-19). Best response was CR in 30 pts (13%) and PR in 29 pts (13%). An ALE occurred in 60 pts (26%), resulting in a 52% overall response rate. SD was seen in 57 pts (25%), 19 pts (8%) had progressive disease, 29 (13%) had early death and 3 pts (1%) were inevaluable for response. Median OS from start of treatment was 5.5 months (range, 0-57.5+), the 1-year survival 28% (95%CI: 22%,34%). Pts with adverse cytogenetics did not differ from those with non-adverse cytogenetics in CR+PR rate nor in median OS. The addition of ATRA to DAC during cycle 2 resulted in similar survival (from start of cycle 2) despite the initial modest response to DAC of these 100 pts. Toxicities of DAC (alone or in combination with ATRA) were predominantly hematologic, no differentiation syndrome was observed. Conclusions: DAC is very well tolerated by older, medically non-fit AML pts, with myelosuppression being the major toxicity. CR+PR was attained by 26% of pts. A frequent ALE and the good feasibility of outpatient maintenance support continued DAC treatment, and the response to DAC combined with ATRA warrants a randomized study. Disclosures: Off Label Use: Decitabine (FDA approved for MDS and AML with up to 30% bone marrow blasts) is used here (at the approved dose and schedule)in AML patients with >30% blasts. ATRA (approved for APL) is used here in non M3 AML patients.

Abstract 2028 Poster Board II-5 Background. Based on the dismal outcome of older patients with ALL and a promising pilot study in a single institution, HOVON started a multicenter phase 2 feasibility study to assess efficacy and safety of a novel chemotherapy regimen for patients between 40 and 70 years of age (younger patients being eligible for a pediatric treatment schedule in a parallel study). The innovative part of the study consisted of a relatively intensive “pre-induction” course for rapid reduction of the tumor load. Treatment schedule. The pre-induction course consisted of cytarabine 200 mg/m2 and etoposide 120 mg/m2 on day 1, and 8 and MTX 500 mg/m2 on day 4, and 11. This was followed on day 15 by an induction course of vincristine 1 mg/wk x 3, dexamethasone 8-12 mg/d x 21 depending on body weight, and adriamycine 40 mg (>60 yr: 30 mg)/m2/d on day 2-4 (ODA). After regeneration of the bone marrow, ODA was repeated once in patients with at least a partial remission. Subsequently, consolidation with cytarabine 1000 mg/m2/12 hr x 4 followed by asparaginase 6,000 IU/m2/d x 10 was given, and, finally, regular maintenance therapy for 30 cycles. Intrathecal prophylaxis consisted of weekly MTX 15 (>60 yr: 10) mg x 4 followed by monthly MTX 15 (> 60 yr: 10) mg x 6. Patients with t(9;22) also received imatinib 600 mg/d, except during asparaginase administration; patients in complete remission (CR) were eligible for nonmyeloablative allogeneic stem cell transplantation (SCT) using either sibling (sib) or matched unrelated donors (MUD). Results. Sixty patients, 27 males and 33 females, with a median age of 57 years (range 40–69) were enrolled; 40% were over 60 years. B-lineage ALL was present in 54. Median WBC count at diagnosis was 6.3 × 109/l (range 0.7-186). t(9;22) was present in 16 (34%) and t(4;11) in 4 (9%) of 47 patients with available karyotype or FISH data. Based on WBC, cytogenetics, and time to CR 31 patients (52%) were considered high risk and 29 (48%) standard risk. Fifty-one patients (85%) attained CR, 47 of them after the first ODA course. One patient was a nonresponder. Ten patients (17%) died during the early phases of intensive chemotherapy mainly due to infection. Moreover, treatment had to be withdrawn or delayed in 12 (20%) because of side effects such as grade 3-4 mucositis and infection. Seventeen patients underwent allo-SCT (10 sib, 7 MUD) in first CR. After a median follow-up of 21 months (range 15–37), 37 patients (62%) were alive; 13 (22%) relapsed, 6 of them after SCT. The 2-year EFS was 48% (95% CI 32-63%), 2-year DFS 51% (32-68%), and 2-year OS 61% (47-73%). Conclusion. Notwithstanding considerable toxicity including early mortality of 17%, this schedule produced high survival and low relapse rates, especially when considering the median age of 57 years and the relatively high number of high risk patients. The pre-induction course induced a rapid reduction of (circulating) blasts in all patients. Based on this phase 2 study a prospective randomized trial has recently been initiated. In order to reduce toxicity the protocol has been amended by replacing dexamethasone by prednisone, allowing time for hematological recovery after the pre-induction course, growth factor support, and optimizing antibiotic prophylaxis. Disclosures: No relevant conflicts of interest to declare.

Patients with a primary or secondary erythrocytosis or iron overload (hemochromatosis, alpha thalassemia) are often treated with phlebotomy to reduce the iron stores. Frequently, repeated phlebotomies are necessary to achieve the treatment target. However, this procedure seldom causes side effects and the desired effect is not always reached. We developed an erythrocytapheresis technique based upon an isovolemic principle that can be used to remove larger amounts of erythrocytes and is experienced as more convenient by the patient.

The HOVON-65/GMMG-HD4 trial is a prospective, randomized phase III trial to evaluate the efficacy of bortezomib prior to high-dose melphalan (200 mg/m2, HDM) on response and progression-free survival (PFS) in patients with newly diagnosed MM stage II or III according to Salmon & Durie (SD). Until May 2008 in total 833 patients aged 18–65 years were included in the trial. Patients were randomized to receive three cycles of VAD (arm A; vincristin 0,4mg, days 1–4, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20) or PAD (arm B; bortezomib 1.3 mg/m2, days 1,4,8,11, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20). Hematopoietic stem cells were mobilized in patients using the CAD regimen (cyclophosphamide 1000 mg/m2 iv day 1, adriamycin 15mg/m2, days 1–4, dexamethasone 40mg, days 1–4) and G-CSF. After stem cell harvesting all patients received one or two cycles of HDM with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) and bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. As of August 2008 stem cell harvesting data from the first consecutively enrolled 150 patients (75 per arm) were analyzed. The data of the initial 300 patients (150 per arm) will be available by November 2008. Both treatment arms did not differ in age, SD stage of disease, ISS stage, and FISH abnormalities. 132 patients (88%) were treated with CAD plus G-CSF. Dosing and type of G-CSF treatment were comparable in both arms. In all patients stem cell collection was successful and at least two autografts could be harvested (minimal number of stem cells permitted per autograft was 2.0 ×106 CD 34+ cells per kg BW). Induction treatment Days until first leukapheresis Median (range) Number of leukaphereses Median (range) Number of harvested CD34+ stem cells (× 106) per kg BW Median (range) PAD 110 (96–149) 1 (1–4) 10.5 (4.1–37.6) VAD 111 (95–156) 1 (1–5) 9.3 (4.0–37.0) In 64% of the patients in arm A (VAD) and 79% of the patients in arm B (PAD) only one leukapheresis was sufficient for stem cell harvesting. In all patients hematopoietic reconstitution was achieved after HDM followed by autografts harvested after PAD or VAD. We conclude that stem cell harvesting after PAD is very well feasible.

The randomised, open-label, phase III trial HOVON-50 was designed to evaluate whether the addition of Thalidomide to AD and HDM would prolong event-free survival (EFS) in patients with newly diagnosed MM. Patients with Salmon & Durie stage II or III, age 18–65 years inclusive were randomly assigned to arm A: 3 cycles of VAD or to arm B, the same regimen but with Thalidomide 200 orally, days 1–28 instead of Vincristine (TAD). Thalidomide was started at day 1 of the first TAD cycle and was stopped 2 weeks before stem cell mobilization was started. Patients in arm B received thrombosis prophylaxis consisting of subcutaneously Low Molecular Weight Heparin (LMWH). Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy all patients were to receive 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with ƒÑ-Interferon (3 „e 106 IU, thrice weekly, arm A) or Thalidomide 50 mg daily (arm B). Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 18 patients were not eligible, while from 2 patients data were incomplete. EFS was defined as time from randomisation to induction failure, progression, or death from any cause. Patients (n=109) who received a non-myeloablative allogeneic transplant after HDM 1 before progression, were censored at the date of allo-SCT; those patients were usually entered into the HOVON-54 trial. Both arms were comparable with regard to age, myeloma stage and prognostic factors. Best responses achieved on protocol were significantly higher in the patients randomized to thalidomide: Minimal PR rates were 87% and 79 % (pULN at diagnosis and higher ISS were identified as adverse prognostic factors for response and survival endpoints. Abnormalities of chromosome 13 as determined by FISH or conventional karyotyping had no prognostic impact. 96 patients (18%) went off protocol treatment without receiving HDM, mainly due to excessive toxicity (5 %), intercurrent death (4%) or ineligibility for further treatment (3%) comparable in both arms. IFN maintenance in 34% of patients of which 23 % stopped due to toxicity. Thalidomide maintenance started in 57% of patients in arm B of which 63% stopped due to toxicity Thalidomide resulted in significantly higher response rates and improved EFS and PFS. However, this did not translate into better overall survival

The prognosis of patients with aggressive mature T cell lymphoma is very poor. We wondered whether the addition of the anti-CD52 monoclonal antibody alemtuzumab to 2-weekly CHOP chemotherapy as 1st line treatment would result in acceptable toxicity, improved response, and outcome. In a multicenter phase II design, 20 patients were to receive 8 cycles of CHOP14 (d 1: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, 2 mg max, and day 1–5 prednisone 100 mg; repeat at day 15). Alemtuzumab 30 mg subcutaneously was added at day 1, 5 and 10 of each cycle (total of 24 administrations). Valaciclovir, cotrimoxazol and fluconazol were given as prophylaxis for herpes viral, PCP and fungal infections, respectively; G-CSF was given to enhance neutrophil recovery. Blood products were irradiated. Monitoring for CMV (re)activation by PCR or pp65 antigenemia was mandatory. Between Nov 2005 and Oct 2007, 20 patients with newly diagnosed T-NHL were included by 10 different centers (55% male; median age 50, range 20 to 65 years; 19 stage III/IV; 11 IPI high/high-intermediate). T-NHL histologies were: peripheral T cell lymphoma NOS (n=10), angioimmunoblastic lymphoma (n=6), subcutaneous panniculitis-like lymphoma (n=3), enteropathy-associated T cell lymphoma (n=1). Patients received a median of 8 CHOP cycles, 85% received 6 or more. Response to treatment was: 12 CR, 6 PR (ORR 85%) and 2 NR. At a median follow-up of 18 months, 11 patients are still alive, 9 patients have relapsed; the median FFS is 20 months (range 2–25) and median OS is 23 months (5–29). Toxicity was considerable, with CMV reactivation in 7/20 patients; one patient developed CMV disease; hospital admissions because of (mostly neutropenic) fever occurred in 8 patients. However, none of these patients died from these adverse events. One patient died in CR, 5 months after treatment due to sepsis complicating an extensive varicella zoster infection. Three patients (two with peripheral T cell lymphoma, one with angioimmunoblastic lymphoma without initial EBV activity) developed an EBV-related lymphoproliferative disorder. These patients ultimately died of relapse T-NHL. In conclusion, an intensive alemtuzumab-CHOP14 regimen is feasible and effective in aggressive T-NHL as far as response and early outcome are concerned. Toxicity, especially the high percentage of herpes viral reactivation including EBV-related lymphoproliferation requires careful monitoring.

Introduction: In 2002 the EORTC and the German MDS Study Group initiated a randomized phase III study comparing low dose Decitabine to supportive care in patients (pts) of 60 years or older with primary or secondary MDS or CMML. MDS patients with either 11–20% BM blasts or ≤ 10% blasts and poor cytogenetics could be included. Pts with a BM blast count between 21–30% without signs of disease progression for at least one month were also candidates for the study. Methods: Patients were centrally randomized; stratification factors were cytogenetics risk group, IPSS, MDS (primary vs secondary) and study centre, The treatment schedule was 15 mg/m2 Decitabine i.v. over 4 hours every 8 hours for the first 3 three consecutive days, of every 6 week-cycle, for a maximum of 8 cycles. Results were evaluated every 2nd cycle. When a complete remission was reached at least another 2 courses were given. The primary endpoint of the study was Overall Survival. AML free survival, Progression Free Survival (PFS), response rate, toxicity and QoL were secondary endpoints. A total of 185 deaths were required to detect a hazard ratio (HR) of 0.66 (alpha=5%, beta=20%). Intent-to-treat analysis was used. Results: Between 10.2002 and 5.2007 a total of 233 pts (149 male and 84 female) were recruited from 40 centres. The median age was 70 (60–90 years); RAEB-t was diagnosed in 32% of the pts. Most pts had an IPSS Intermediate-2 (55%) or high risk (38%). Poor risk cytogenetics was found in 46% of the patients. Prior therapy for MDS (not being intensive chemotherapy) was given in 20% of pts. The randomized groups were well balanced regarding stratification factors, age and FAB classification. The median follow up was 2.5 years. Time to Off Study was 180 (Decitabine) vs 112 days (SC arm). The median number of cycles given to the patients was 4 with 40%getting no more than 2 cycles. In a significant number of pts, subsequent treatment, consisting of transplant (10%) or induction chemotherapy (11%), was given. The distribution of best response in Decitabine vs SC arm was CR (13% vs 0%), PR (6% vs 0%), HI (15% vs 2%), SD (14% vs 22%), PD (29% vs 68%), hypoplasia (14% vs 0%), inevaluable (8% vs 8%). The 18 pts on Decitabine with a HI showed the following responses: 3-lineage (n=7), 2-lineage (n=5) and 1-lineage (n=6). The median time to response (CR/PR/HI) was 0.32 yrs and the response duration was 0.72 years. Median OS was 0.84 (Decitabine) vs 0.71 years (SC arm), estimated HR was 0.88, 95% CI 0.66–1.17, p=0.38 (logrank 2-sided). The PFS was significantly (p=0.004) longer in Decitabine vs SC arm: median was 0.55 vs 0.25 years, HR=0.68 (95% CI 0.52–0.88). Time to AML or Death was not significantly improved (p=0.24): median was 0.73 vs 0.51 years (HR=0.85, 95% CI 0.64–1.12). Toxicity. The toxicity was mainly cytopenia related toxicity that was either disease related or hematotoxicity; CTC grade 3–4 febrile neutropenia was 26% (Decitabine) vs 7% (SC arm) and Grade 3–4 infection was 59% vs 47%. Differences in non hematologic toxicities were mainly gastrointestinal: grade 1–2 nausea (28% vs 16%) and grade 1–2 vomiting (16% vs 9%). During the study period, 29 (Decitabine) vs 25 (SC arm) patients died: due to either progression to MDS/AML (7 vs 20), toxicity (9 vs 0), progression and/or toxicity (10 vs 1), other reasons (3 vs 4). Conclusions. Decitabine was found to be an effective drug in these high risk MDS patients with a overall RR of 34%, (similar to earlier studies), leading to a significant PFS improvement as compared to SC arm. The difference Decitabine vs SC arm regarding time to AML or Death was not significant. Due to shorter treatment duration (not being continued beyond 8 cycles) and maybe also due to subsequent treatments administered after disease progression, the difference regarding OS was lower (HR=0.88) and not statistically significant.

Background: AL amyloidosis is generally caused by a kappa or lambda light-chain producing plasma cell clone in the bone marrow. High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is effective in AL amyloidosis. Pretreatment of these patients with vincristine, doxorubicin and dexamethasone (VAD) may have a rapid and additive effect on the underlying plasma cell clone. Objective: To study the feasibility and efficacy of VAD followed by HDM and ASCT in AL amyloidosis. Patients and Methods: In a prospective multicenter phase II study, the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) studied the effect of three courses of VAD followed by HDM with ASCT on hematological and clinical response rates and overall survival in AL amyloidosis. Untreated patients aged ≤ 65 years with proven AL amyloidosis and monoclonal gammopathy or multiple myeloma stage I were included. Patients with recent prior malignancy, other types of amyloidosis, and severe other diseases not related to AL amyloidosis were excluded. High risk was defined as cardiac septum ≥ 15 mm, cardiac ejection fraction ≤ 55%, creatinine > 177 μmol/L, or bilirubin > 34 μmol/L (Dispenzieri et al, J Clin Oncol2001; 19:3350–6). All patients were treated with VAD or dose-modified VAD and after the third course re-evaluated. Patients were judged eligible for stem cell collection and ASCT if WHO performance status 0–2, NYHA class 1–3, cardiac ejection fraction >45%, and no severe other disease. Hematological response was defined as complete response (disappearance of monoclonal protein in blood and urine, and no clonal excess of plasma cells in bone marrow), partial response (greater than 50% reduction in serum and urine monoclonal proteins), persistence, and progression (doubling of monoclonal protein in serum or urine). Clinical response was defined as organ response, stabilization, or progression (Gertz et al, Am J Hematol2005; 79:319–28). Results: Sixty-nine newly diagnosed patients with AL amyloidosis were included between September 2000 and January 2006: 37 men and 32 women with a median age of 55 years and WHO performance status 0–2. Organ involvement was renal in 58 (84%), cardiac in 32 (46%), hepatic in 12 (17%), and neuropathic in 18 (26%); 15 patients (22%) had involvement of 3 or 4 organs. Thirty-seven (54%) could be classified as high-risk patients. Forty-six patients (67%) could proceed to HDM (140–200 mg/m2) after VAD induction. The transplants were performed in tertiary referral centres. Median haematological recovery time of ANC > 1.0 × 109/L and platelets > 50 × 109/L was 17 and 21 days, respectively. End of survey was November 2007. Overall hematological response was 39% including 16% with a complete response. Overall clinical response was 26% and stabilization in 35%. In 43% of patients only the clinical response could be assessed. Overall survival of all patients was median 60 months and had not been reached for the transplanted patients (Figure). Nine patients died from TRM (11%), 7 during VAD and 2 following HDM. Side effects CTC grade ≥ 2 were recorded in 46% of patients during VAD induction and in 87% of patients after HDM; infections CTC grade ≥ 2 were recorded in 13% and 65%, respectively. Conclusions: VAD induction followed by HDM and ASCT for AL amyloidosis is feasible, has acceptable TRM, and results in a remarkable prolonged survival. This two-step approach of induction with non-intensive chemotherapy in all patients followed by HDM with ASCT in eligible patients is now recommended as standard treatment by HOVON for newly diagnosed patients with AL amyloidosis who are eligible for high-dose therapy. Figure Figure

Introduction: In older patients with AML in whom conventional chemotherapy is not indicated (comorbidities, performance status, poor cytogenetics etc.), treatment with low-dose azanucleoside DNA demethylating agents may be a less intensive alternative. In MDS, these drugs need to be administered over a prolonged time period in order to gain full benefit, since delayed responses are common, and thus occur not infrequently after more than 6 months of treatment. In a phase II multicenter trial (00331) of low-dose decitabine (DAC, 135 mg/m2 administered over 3 days in 9 intravenous 3-hour infusions, with 15 mg/m2/infusion, repeated every 6 weeks) patients benefiting from this treatment were offered an outpatient maintenance with the drug given at an even lower dose and as one-hour infusions on 3 consecutive days. Patients and Methods: Patients having completed 4 courses of DAC according to the study protocol and being in complete or partial remission (CR, PR), having achieved an antileukemic affect or stable disease were offered continued DAC treatment with 20 mg/m2 given intravenously over one hour on 3 consecutive days, repeated every 6 to 8 weeks. Maintenance treatment was continued until relapse or progression. Results: Of the 235 patients included in the 00331 study, 57 (25%) received the 3-day DAC maintenance. Median age of these 57 patients before study inclusion was 71 years (range 60 – 81), the median white blood count 4200/μl (range 0.2–285,000/μl), 59% had preceding MDS, with a median of 16 months duration. Performance status before initial treatment with DAC: ECOG 0, 1 and 2 in 29%, 58% and 13% of the patients, respectively. 60% had intermediate-risk cytogenetics, 28 % poor-risk cytogenetics, no metaphases were obtained or cytogenetics not done in 12 %. Remission status at maintenance start, i.e. response to 4 courses of DAC, was CR+PR in 71 % of the patients. A median number of 4 maintenance courses was administered (range, 1–16), with 24 patients (42 %) receiving 5 or more courses. Treatment was overall very well tolerated, with dose reductions because of cytopenia necessary in Conclusions: Since the relapse rate in MDS and AML after stopping of azanucleoside treatment is very high, continued dosing, e. g. as a maintenance treatment may significantly prolong disease control. This 3-day “very low-dose” DAC regimen (60 mg/m2 total dose per course) could be given over 4 or more courses in the majority of these AML patients already pretreated with higher doses of the drug, even in the presence of poor-risk cytogenetics. The good tolerance and feasibility of the schedule indicates that it may also be useful in maintaining remissions obtained by a standard treatment of AML/MDS.

Few therapeutic options exist for older, unfit AML patients (pts) who often have poor cytogenetics. We initiated a phase II trial in untreated AML pts >60 years ineligible for induction. 1° endpoint was best response: complete (CR) or partial remission (PR) or an antileukemic effect (ALE, >25% bone marrow [BM] blast reduction). 2° endpoints: overall survival (OS), toxicity. Low-dose DAC was given as for MDS (i.e. 135 mg/m2 i.v. over 72 hrs), repeated q 6 weeks for up to 4 courses, with all-trans retinoic acid (ATRA, 45mg/m2/day for 28 days) given during course 2 in pts with ALE or stable disease (SD). Maintenance with 20 mg/m2 DAC i.v. over 1 hour on 3 days (total dose 60mg/m2, outpatient administration) q 6–8 weeks was offered to pts completing all 4 courses. Pts with a WBC of >20 000/μl received a short course of hydroxyurea (HU) prior to DAC. Pts requiring HU beyond day 28 of course 1 and/or showing blast increase had progressive disease (PD). In pts with high absolute peripheral blood blasts, RNA from these cells was isolated sequentially (day 0, 2, 5), with CD34 selection in 2 pts, for global expression studies. At time of this analysis, 155 fully evaluable pts have been recruited (median age 72.5 yrs, range 56–85). 39% of pts were >74 yrs. Poor-risk cytogenetics and/or preceding MDS were present in 32 and 49%, respectively. Median WBC before treatment was 4800/μl (range, 400-241,000, >20,000/μl in 25%, >50,000/μl in 10%). Median BM blasts were 56% (25–100). A median of 2 courses was given. 69 pts received ATRA. 41 pts received a total of 162 maintenance courses (median 3, range 1–11). Best response was CR in 23 pts (15%) and PR in 15 pts (10%). An ALE occurred in 45 pts (29%), resulting in a 54% overall response rate. SD was seen in 37 pts (24%), 15 had PD (10%), 20 pts early death (13%). CR+PR rate by cytogenetic subgroups: with normal karyotype 18/51 (35%), with poor-risk 9/46 (20%) and with other abnormalities 6/36 (17%). Toxicities of inpt DAC were very similar to those described for MDS (neutropenia, fever/infection, pancytopenia). No unexpected toxicities or ATRA syndrome were observed with the combination of DAC+ATRA. Median OS from start of treatment was 5.5 months (range, 0.3–38+), the 1-year survival 26%. Cytogenetic subgroups did not differ in median OS. Affymetrix HG-U133 Plus 2.0 microarrays of 9 pts revealed transcription changes (both induction and repression of large sets of genes): between 53 and 256 previously silent genes were reexpressed. Conclusions: low-dose DAC is very well tolerated by older AML pts ineligible for more aggressive treatment, with myelosuppression being the major toxicity. In vivo reexpression of genes was noted in leukemic blasts. Complete and partial remissions occured in 25% of pts. A frequent antileukemic effect and the good feasibility of outpatient maintenance support continued DAC treatment.

Introduction: Conventional phlebotomy is the standard therapy to remove either erythrocytes or iron in patients with Polycythema Vera (and sec. polyglobulinemia) or patients with hemochromatosis (HC) (and iron overload). This treatment that should be repeated regular has its side effects, is often experienced as inconvenient by the patients and the desired effect is not always reached. We developed an erythrocytapheresis technique based on an isovolemic principle that can be used to remove larger amounts of erythrocytes and is experienced as more convient by the patients. Here we report our experience and compare conventional phlebotomy with either a removal of a the fixed volume of 500 ml or with an exchange volume based on a decrease in Ht ordered by the haematologist. Technique: The erythrocytapheresis was performed according to the standard procedure using a Cobe Spectra. The establish an isovolmic procedure the removed erythrocyte volume was replaced by albumin and ACD anticoagulant with either a volume of 500ml or with a calculated volume to reach the desired Ht. Patients: 29 patients (14 male, 15 female) were entered in this study with a median age of 57 years (range 20–80years). 14 patients were diagnosed as PV patients, 10 with HC, 4 with sec. polyglobulinemia and 1 with sec. iron overload. In 10 patients this therapy was started for reasons of intolerance or insufficient result of repeated phlebotomy. In 19 patients it was used as front line therapy before cytoreductive treatment was started or as supportive care. Results: A total number of 137 procedures were performed. 105 with a fixed volume of 500 ml and 32 with a calculated volume based on the desired decrease of the Ht. The maximum number of procedures was 22 in a patient with phlebotomy resistant HC. All procedures were performed without any clinical problems and experienced as more convenient by those patients who could compare these techniques. In 14 PV patients 47 procedures were performed with a median removal of 16% of the total erythrocyte volume. Compared with conventional phlebotomy this was an improvement in 12 patients with a median increase in erythrocyte removal of 58% (range −14%–81%). In the 10 HC patients 69 procedures with median erythrocyte volume removal of 535 ml was performed. This was a median removal of 22% (range 17–24%) of the total erythrocyte volume and an improvement of median 140% (range 65–216%) compared with phlebotomy. In the other 5 patients the median removed volume was 13% (11–16%) with an improvement of 13% (range 11–16%). The erythrocyte volume removed with the patient tailored volume exchange were all within the range of the volumes removed with the fixed exchange volume technique. Conclusions: Isovolemic erythrocytapheresis is a save and efficient technique either to removed large volumes of erythrocytes or to treat iron overload. Patient tailored volume removal is as yet not more efficient as the fixed volume procedures. Probably this technique can be improved further both technically and by removal larger amounts of erythrocytes.

The joint phase-III HOVON50/GMMG-HD3 trial was designed to assess the effect of thalidomide in induction treatment and as maintenance after high-dose therapy (HDT) and autologous stem cell transplantation (SCT) for multiple myeloma (MM). The standard treatment arm comprised 3 cycles of VAD, mobilisation with CAD+G-CSF (cyclophosphamide 1000 mg/m2, day 1; adriamycin 15 mg/m2, days 1–4; dexamethasone 40 mg, days 1–4; G-CSF until end of harvest), HDT with 1 or 2 cycles of melphalan 200 mg/m2, followed by autologous peripheral blood SCT (PBSCT), and maintenance with interferon-alpha (9 mio. U per week). In the experimental arm, TAD (thalidomide, 200 mg for HOVON / 400 mg for GMMG; adriamycin 9 mg/m2, days 1–4; dexamethasone 40 mg, days 1–4, 9–12, 17–21) was used for induction treatment. Mobilisation and HDT were identical to the standard arm. Experimental maintenance was thalidomide (50 mg per day). A first group of 406 patients (of 1050 included) are evaluable for the comparison of VAD vs. TAD and response after 1st HDT. A trend for a higher toxicity was observed in the TAD- compared with the VAD-arm (drop out: 15% vs. 8%, p= 0.10). Low molecular weight heparin was effective in the prevention of deep venous thrombosis during TAD-treatment (DVT-incidence 8% vs. 4% p= 0.15). The median number of stem cell collections to harvest at least one autograft was 1 in both arms (p= n.s.). Treatment-results are presented in table 1. In a subgroup of 90 GMMG-patients, 78% and 74% compared with 62% and 54% still received thalidomide compared with interferon-alpha at 12 and 24 months after start of maintenance. In summary, thalidomide+AD induce a significantly higher response rate, but this effect is completely offset by HDM. Therefore, results on EFS/PFS are necessary before thalidomide containing regimens can be defined as a standard for induction treatment before HDT. The maintenance treatment with thalidomide is better tolerated compared with interferon-alpha. | | After VAD | After TAD | p-value | || | PR | 60% | 73%

High-risk Non-Hodgkin lymphoma (NHL) in elderly patients (> 60 yrs) is associated with a relatively low complete response (CR) rate and a poor overall survival (OS). Previous studies have shown that addition of Rituximab to standard CHOP chemotherapy may improve CR and/or OS. A similar improvement has been shown for intensification of CHOP from 21 day intervals to 14 day intervals. The Dutch HOVON group and the Nordic lymphoma group have performed a multi-center, randomized phase III trial to compare 8 cycles of intensified CHOP (CHOP14) with the same regimen plus 6 administrations of Rituximab in previously untreated elderly patients with intermediate or high-risk NHL. Inclusion criteria were diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma grade III; intermediate or high-risk NHL according to age adjusted IPI score; CD20-positive NHL; age 65 yrs or higher. The target number was 400 patients to be accrued in 5 years based on an expected increase in event-free survival with hazard ratio HR=0.70. Aplanned interim analysis was performed after inclusion of 250 patients, restricted to 211 patients included from 1st September 2001 to 1st October 2004. Forty patients had to be excluded because of lack of treatment and evaluation data, leaving 171 patients for the analysis. The median time off protocol treatment was 119 days (range 4–468 days). The median age was 73 years (range 62–88 years). There was no difference between the two treatment arms regarding histology, age, WHO classification of NHL, age-adjusted IPI score, Ann Arbor stage, WHO performance status and serum LDH. There was no significant difference of toxicity or CR between the two treatment arms. However, a highly significant difference was observed for event-free survival and overall survival in favor of the treatment arm with CHOP plus Rituximab. Based on this interim analysis, the randomization was halted and patients in the control arm were further treated with CHOP plus Rituximab. Since the outcome of the interim analysis could be biased due to incomplete data, a final decision to stop the trial awaits a new analysis which is planned for 26th August 2005 after collection of missing or incomplete data. If the new analysis confirms the results of the interim analysis, i.e. that Rituximab significantly improves the outcome of treatment in elderly patients with intermediate or high-risk NHL, even when an intensified CHOP regimen is used, the study will be closed and outcomes will be presented.

At low doses, azanucleosides with DNA methyltransferase inhibitory activity like 5-azacytidine and 5-aza-2′-deoxycytidine (DAC) have significant single-agent activity in MDS and AML. However, the optimal treatment duration is still a matter of debate: while at least two consolidating courses after best response are usually performed, the response to treatment with these drugs after a relapse of MDS has not been systematically studied. We report on 22/91 patients (pts) with MDS (24%) having received DAC both initially and, at relapse, as re-treatment. Median age was 71 years (range, 51–81). Characteristics of MDS at time of initial treatment according to FAB: 3 RA, 10 pts with RAEB, 8 pts with RAEB-t (i.e. AML according to WHO) and 1 pt with CMML. According to the IPSS at time of initial treatment, 5/22 (23%) pts were intermediate-1 (int-1), 4/22 (18%) pts int-2 and 13/22 (59%) pts were high-risk. Patients had initially received a median of 6 DAC courses (range, 2–6), in 12/22 (55%) pts resulting in a complete remission (CR), in 6/22 (27%) pts in a partial remission (PR) and in 4/12 (18%) pts in hematologic improvement (HI). 6/12 pts. with hematologic CR had also had a complete cytogenetic response. Re-treatment of relapse with DAC started a median 11 months (range, 3–27) after the last course of initial treatment. Characteristics of MDS at time of re-treatment: 1 pt RA, 13 pts RAEB, 6 pts RAEB-t and 2 pts sAML. During re-treatment, pts received a median of 3 courses (range, 1–6), with 10/22 (45%) responses: 1 CR, 2 PR (all 3 had CR at initial treatment) and 7 HI (2 CR at initial treatment, 4 PR, 1 HI). 12/22 (55%) pts did not show objective responses to re-treatment, including 3 with primary resistance to the first re-treatment course. Median survival of all pts (n=22) from start of first DAC course was 28 months (range, 15–50+) 13/22 (59%) pts transformed to AML. Median time from second response to relapse was 4 months (range, 1–16), thus three times shorter than first response. The pt with CR both at initial treatment (9 months duration) and at re-treatment (5 months duration) received a second re-treatment with 3 courses of DAC (total of 15 courses), without achieving another response. Compared to pts not achieving a second response, responders to DAC re-treatment were less frequently in the IPSS high-risk group (40% versus 83%), and had lower median sLDH at re-treatment start (197 U/L versus 282 U/l). Age, FAB subtype at retreatment, previous response to DAC (including response duration and achievement of a cytogenetic remission) did not differ between both groups. In conclusion, re-treatment resulted in objective responses in 45% of previously DAC-responsive patients. However, quality and duration of second remissions were inferior, implying that DAC-responsive patients might benefit more from continuation of the initial treatment than from re-treatment. Ongoing multi-institutional trials allow continuation of initial DAC treatment beyond 6 courses.

In acute myeloid leukemia the leukemic cells are thought to be blocked in their normal differentiation. The stage of differentiation is the basis for the FAB classification. Induction of cell differentiation is a new and promising development in the treatment of some myeloproliferative diseases. The criteria for cell maturation and differentiation are almost all based on the morphology of the leukemic cells. In this study we tried to specify the maturation stage of the leukemic cells by quantitative enzyme analysis. In the HL60 (promyelocytic) cell line cells we determined the following enzymes: myeloperoxidase; alpha naphthyl acetate esterase; alpha naphthyl butyrate esterase and lactate dehydrogenase. The enzyme profiles obtained after culturing the cells in the presence of the differentiation inducing agents 1 : 25 dihydroxy vitamin D3 and DMSO were compared with several cytochemical and functional parameters. The results obtained in this study show that quantitative enzyme analysis is a useful tool in the study of myeloid or monocytic differentiation.

Cytosine-arabinoside (ARA-C) in low doses induces complete remissions in myelodysplastic syndromes and acute leukemia. Evidence is accumulating that these remissions are not reached by differentiation induction but through cytotoxicity. In HL60 cells differentiation was measured by a comprehensive panel of quantitative and qualitative markers of maturation. After exposure to ARA-C (10(-7) M) for 4 days HL60 cells did not mature morphologically. Cell volume increased. The increase in esterase activity was small and did not reach the amount measured in normal monocytes. There was no significant difference in latex phagocytosis and NBT reduction between cultures with and without ARA-C. HL60 cells were arrested in S-phase and clonogenic capacity persisted. The observed changes after exposure to ARA-C seem to be caused by impeded cell division while synthesis of protein continues. We conclude that ARA-C in low dose exerts its effect by halting proliferation through cytotoxic effects and not by differentiation induction.