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Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

Objectives:High-resolution manometry (HRM) is the preferred method for the evaluation of motility disorders. Recently, an update of the diagnostic criteria (Chicago 3.0) has been published. The aim of this study was to compare the performance criteria of Chicago version 2.0 (CC2.0) vs. 3.0 (CC3.0) in a cohort of healthy volunteers and symptomatic patients.Methods:HRM studies of asymptomatic and symptomatic individuals from several centers of Spain and Latin America were analyzed using both CC2.0 and CC3.0. The final diagnosis was grouped into hierarchical categories: obstruction (achalasia and gastro-esophageal junction obstruction), major disorders (distal esophageal spasm, absent peristalsis, and jackhammer), minor disorders (failed frequent peristalsis, weak peristalsis with small or large defects, ineffective esophageal motility, fragmented peristalsis, rapid contractile with normal latency and hypertensive peristalsis) and normal. The results were compared using McNemar’s and Kappa tests.Results:HRM was analyzed in 107 healthy volunteers (53.3% female; 18–69 years) and 400 symptomatic patients (58.5% female; 18–90 years). In healthy volunteers, using CC2.0 and CC3.0, obstructive disorders were diagnosed in 7.5% and 5.6%, respectively, major disorders in 1% and 2.8%, respectively, minor disorders in 25.2% and 15%, respectively, and normal in 66.4% and 76.6%, respectively. In symptomatic individuals, using CC2.0 and CC3.0, obstructive disorders were diagnosed in 11% and 11.3%, respectively, major disorders in 14% and 14%, respectively, minor disorders in 33.3% and 24.5%, respectively, and normal in 41.8% and 50.3%, respectively. In both groups of individuals, only an increase in normal and a decrease in minor findings using CC3.0 were statistically significant using McNemar’s test.Discussions:CC3.0 increases the number of normal studies when compared with CC2.0, essentially at the expense of fewer minor disorders, with no significant differences in major or obstructive disorders. As the relevance of minor disorders is questionable, our data suggest that CC3.0 increases the relevance of abnormal results.

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m2/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19–74 years) with de novoAML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2–4 and grade 3–4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).

Formaldehyde has been known for many years as an indoor air pollutant coming from different pieces of furniture and panels in the rooms.A study of the concentrations of formaldehyde in the air of sixty selected structures panelled with urea-formaldehyde resins was carried out in Spain. Air samples were collected in impingers and analyzed by 3-Methyl-2 Benzothiazolone-hydrazone-hydrochloride tests (M.B.T.H.) during the year 1984.The average concentration of formaldehyde was 552 μg/m3 with a range of 41-2823 mg/m3. Thirty-nine homes were found to have concentrations exceeding the average value. These concentrations are higher than allowed indoor exposure standard.Health information was received by direct contact from individuals. Eye irritation, dry or sore throat, mucous membrane irritation, burning eyes, sneeze, runny nose, rash, cough, conjunctivitis, difficult breathing, pharyngytis, bronchitis, headache, weakness, vomiting, nausea, photophobia ... were the most frequent symptoms reported by the occupants.A complementary study was carried out using information on type of structure, age and heating systems of the building.Statistically significant relationship was observed between formaldehyde concentration and health data and between formaldehyde levels and installation age of panels in the structures.

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/µL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA?CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/µL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA?CT. In patients with initial WBC less than 5,000/µL and allocated to ATRA?CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/µL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P= .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% ± 10%, 63% ± 8%, and 68% ± 7% in patients who had ATRA syndrome as compared with 15% ± 3%, 77% ± 2%, and 80% ± 2% in patients who had no ATRA syndrome (P= .05, P = .003, and P = .03), respectively. In a stepwise Cox model that also included pretreatment prognostic variables, ATRA syndrome remained predictive for EFS and survival. In conclusion, in this multicenter trial where CT was rapidly added to ATRA in case of high or increasing WBC counts and DXM generally also used at the earliest clinical sign, the incidence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival. © 1998 by The American Society of Hematology.

214 patients among 282 consecutive admissions had at least one measurement of serum albumin (SA) during their stay on the ICU and were classified according to their stay on the ICU and were classified according to their lowest value of SA. Mean SA was 2.88±0.74 g/100 ml. Survivors had a mean SA (3.18±0.60) higher than non-survivors (2.35±0.68 g/100 ml) (p<0.05). 64% of patients were admitted with an abnormally low SA (less than 3.5 g/100 ml) and in 56% of these the initial value was higher than the last. Mortality increased in the groups with lower SA and the level of SA was associated with infection (x2=73.9) and mortality (x2=69.7) (p<0.05). The percentage of infected patients who died increased in groups with lower SA.

An unusual complication from the simultaneous use of two central venous catheters and a Swan-Ganz flow-directed balloon-tipped catheter is described.

Introduction and Objectives. Lenalidomide is a new inmunomodulatory drug which has shown effectiveness, in combination with dexamethasone, in relapsed or progressive Multiple Myeloma (MM). In our country, little experience outside clinical trials exists since lenalidomide is only currently available in the compassionate use program, for patients with advanced MM. With the purpose of sharing the clinical practical experience with this drug, we considered it interesting to gather the outstanding data on the use of lenalidomide in a multicentric registry, throughout the Spanish scope. We present the preliminary results of this registry. Patients and methods. We designed a registry, canalized through GEM-PETHEMA, in which main clinical data of MM patients relapsed or progressive treated with lenalidomide within the compassionate use program, were collected. The decision to treat these patients was prior to and independent of the decision to make this registry and was only based on clinical criteria. The selected patients had at least one response assessment. Results. 19 valid questionnaires have been received, 14 patients (pts.) being assessable for response. The treatment was started between 03/06 and 04/07. Average age: 63 years (40–77); 9 men and 5 women. Type of MM: IgG 9 pts, IgA 3 pts, 1 non-secretory, 1 Bence Jones K. Average M-protein 3.25 g/dL(SD: 3,32); average creatinine 1,05 (SD: 0.36); average bm plasma cells infiltration: 36%. Median lines of previous treatments: 4 (2–8). 13 pts had received bortezomib, 8 pts had received thalidomide, and 7 had undergone autologous PBSCT. 7 pts showed extramedullary plasmocytomas.2 patients received the standard dose (25 mg daily, P.O. 21 days every 4 weeks). 2 patients received lower doses. All the patients, except one, received Dexamethasone simultaneously (average 56 mg per week). Prophylaxis for DVT: 7 pts with LWMH and 3 pts with salicylates. 4 patients did not receive prophylaxis. At the time of data collection 10 patients where still on the treatment. Lenalidomide was discontinued in 2 patients due to progression (median time to progression 6 months (1–8); 1 pts underwent PBSCT after reaching PR and discontinued the treatment due to stable disease after 6 months. Response: 2 CR (14%), 1 VGPR (7%), 6 PR (43%), 3 SD (21%). Among the 9 pts with a favorable response (64%): 8 had previously received bortezomib, 4 had received thalidomide, and 4 had undergone PBSCT - Toxicity: Neutropenia G3: 5 pts/G4: 2 pts; 5 patients needed G-CSF. Thrombocytopenia G3: 3 pts/G4: 3 pts. Skin rash in 1 pt. Neither TVP/TEP nor neutropenic fever were observed. Conclusions. Although a more detailed analysis and a longer follow-up is needed the results of our registry are consistent with other published clinical trials: lenalidomide associated with dexamethasone induces durable objective responses in a high percentage of patients with relapsed or progressive MM, after several treatment lines. The tolerance of this drug is acceptable, being the mielosuppression the most relevant toxicity. The role of this drug at low dose for long term maintenance have to be investigated.

Although autologous transplant is the election in poor prognosis patients with Non Hodgkin agressive histologies, some patients relapse, for others collection of progenitor cells is not possible and in some categories as Mantle Cell Lymphoma results after autologous transplant are dismal. From 1999, three prospective multicenter trials with non-myeloablative allogeneic transplant in hematological malignancies have been performed in Spain. Up to now, 36 patients have been registered in these trials. From them,28 (58%)had aDBLCL,1 (3%) a transformed MZL,1 (3%) a BL and 14 (37%) a MCL. The conditioning regimen consisted of fludarabine 30 mg /m2 intravenously (IV) on days −8 to −4 followed by melphalan 70–140 mg/m2 IV on days −3 and−2. The last 25 patients enrolled in the latest trial received rituximab 375mg/ m2;on days −8, −1,+8 and +15 as part of conditioning; filgrastim stimulated peripheral blood stem cells were infused on day 0. GVHD prophylaxis consisted of cyclosporine A (CsA) from day −7 plus short-course methotrexate (MTX) (10mg/m2, days +1, +3, +6), followed by folinic acid rescue. Median age was 51 years (range 27–68);at transplant 5 (13%) of the patients were in CR1, 4 (11%) in a later CR and 29 (76%) had active disease 18 (47%) had sensitive disease and 11 (29%) resistant disease. Days to reach more than 500x 109 granulocytes and more than 20000x109 platelets were +14 (range 10–93) and +12(range 8–18). At a median time of 25 days (range 19–97), 19 patients (50%) developed acute GVHD (13 patients (34%) grade II–IV). At a median time of 107 days(80–267), 68% out of 19 patients at risk developed cGVH being extensive in 11 (39%)Disease was evaluated at day +100 and at that moment 23 patients(65%) were in CR (including 4 / 8 patients transplanted on PGR), 4% in PR and 23% have died due to NRM(Non relapse mortality). With a median follow up of 31 months (range: 6–67 months), 19 patients (50%) are alive, 17 disease free and 19(50%) have died, 10(26%) due to NRM and 8 (21%) due to progression with a proyected NRM at 1 year of 22%. OS and EFS at 5 years of of 43 and 36% respectively. None of the variables analysed influenced on NRM. Regarding efficacy of transplant in different histologies, OS and DFS for MCL were 71% and for BDLCL, 31% and 20% respectively. In this preliminary analysis results in MCL are quite good however for patients with DLBCL should be improved. severe toxicity is still present and to date it should be performed only in the setting of well designed clinical trials.

Background: APL is predominantly associated with low WBC counts. APL with very high WBC counts, i.e. >50 × 109/l, is rare, generally associated with severe coagulopathy and, before the ATRA era, was generally fatal due to early death or subsequent relapse. Methods: we report characteristics and outcome of APL with WBC >50 × 109/l enrolled in two consecutive multicenter trials (APL93 and APL2000) treated with ATRA-CT combinations. In both trials (Blood1999;94:1192, JCO2006;24:5703) pts with WBC >10×109/L received ATRA combined upfront to DNR+AraC followed by 2 consolidation DNR+AraC courses and, in APL93 trial, randomisation for maintenance to intermittent ATRA, continuous low dose CT (6MP+MTX), both treatments (ATRA+CT) or no treatment. In APL2000, they all received maintenance with ATRA +CT, high dose DXM during induction (to further prevent ATRA Sd), and CNS prophylaxis. Results: Of the 1031 pts included in both trials, 261 (25%), 65 (6.4%) and 14 (1.3%) pts had WBC >10×109/l, 50×109/l and 100×109/l, respectively (resp). As compared to pts with<10×109/l and 10–50×109/l, pts with WBC >50×109/l were younger (48 vs. 44 vs. 40.5 years, p=0.002), had lower baseline plt counts (36 vs. 24.5 vs. 27×109/L, p=0.0002) fibrinogen level (1.8 vs. 1.3 vs. 1.2 g/L, p<0.0001) more often M3 variant (6.7 vs. 27.7 vs. 58.8%, p<0.0001) and BCR3 breakpoint (27.8 vs. 39 vs. 56.4%, p<0.0001) whereas CR rates were 94%, 91% and 87%, resp (p=0.054). All failures were due to early death (ED). 8 (13%) ED occurred in pts with WBC>50×109/L, 6 of them due to ATRA Sd and 1 to bleeding. In pts with WBC > 50×109/l, ED was 6/33 (18%) in APL93 and only 2/32 (6%) in APL 2000 trial (p= 0.25). Thus in APL 2000 trial, the CR rate increased to 94% in pts with WBC>50×109/l (vs. 95% in other pts). 2 year incidence of relapse (CIR), EFS and overall survival (OS) were 31.3%, 17.3%, 8.7% (p<0001), 55.4%, 73%, 82% (p<0.0001) and 62%, 83%, 82% (p=0.0002) in pts with WBC >50, 10–50, <10×109/l, resp. However, in pts with WBC> 50×109/l, only 6/38 (15.7%) of those who received combined maintenance (ATRA + CT) relapsed, vs. 12/16 (75%) of those with no or single maintenance (p<0.001). Therefore in pts who received combined maintenance, there was only a trend for higher 2 year CIR in pts with WBC> 50×109/l: 15.7% (vs. 6.4% and 11% in pts with WBC>10–50 and <10×109/l resp, p=0.067) while 2 year OS did not differ between the 3 groups (87% vs. 91% vs. 89.6%, p=0.86). Post-consolidation PML-RARA RT-PCR, available in 33 WBC>50×109/l pts, was positive in 5 (all relapsed), and negative in 28 (6 relapsed). The 19 relapses in pts with WBC> 50×109/l occurred after a median of 11 months, and included 2 CNS relapses (both in APL93 trial). 16 of those pts achieved CR2, most before the arsenic era. 2 y-OS after relapse was 62%. Conclusion: APL pts with WBC >50×109/l are rare, may achieve CR rates similar to pts with lower WBC with improved supportive care (including systematic DXM?). They have only a trend for higher risk of relapse with combined ATRA+CT maintenance, and possibly CNS prophylaxis.

Although autologous transplant is the election in poor prognosis patients with Non Hodgkin agressive histologies, some patients relapse, for others collection of progenitor cells is not possible and in some categories as Mantle Cell Lymphoma results after autologous transplant are dismal. From 1999, three prospective multicenter trials with non-myeloablative allogeneic transplant in hematological malignancies have been performed in Spain. Up to now, 36 patients have been registered in these trials. From them,28 (58%)had aDBLCL,1 (3%) a transformed MZL,1 (3%) a BL and 14 (37%) a MCL. The conditioning regimen consisted of fludarabine 30 mg /m2intravenously (IV) on days −8 to −4 followed by melphalan 70–140 mg/m2IV on days −3 and−2. The last 25 patients enrolled in the latest trial received rituximab 375mg/ m2;on days −8, −1,+8 and +15 as part of conditioning; filgrastim stimulated peripheral blood stem cells were infused on day 0. GVHD prophylaxis consisted of cyclosporine A (CsA) from day −7 plus short-course methotrexate (MTX) (10mg/m2, days +1, +3, +6), followed by folinic acid rescue. Median age was 51 years (range 27–68);at transplant 5 (13%) of the patients were in CR1, 4 (11%) in a later CR and 29 (76%) had active disease 18 (47%) had sensitive disease and 11 (29%) resistant disease. Days to reach more than 500x 109granulocytes and more than 20000x109platelets were +14 (range 10–93) and +12(range 8–18). At a median time of 25 days (range 19–97), 19 patients (50%) developed acute GVHD (13 patients (34%) grade II–IV). At a median time of 107 days(80–267), 68% out of 19 patients at risk developed cGVH being extensive in 11 (39%)Disease was evaluated at day +100 and at that moment 23 patients(65%) were in CR (including 4 / 8 patients transplanted on PGR), 4% in PR and 23% have died due to NRM(Non relapse mortality). With a median follow up of 31 months (range: 6–67 months), 19 patients (50%) are alive, 17 disease free and 19(50%) have died, 10(26%) due to NRM and 8 (21%) due to progression with a proyected NRM at 1 year of 22%. OS and EFS at 5 years of of 43 and 36% respectively. None of the variables analysed influenced on NRM. Regarding efficacy of transplant in different histologies, OS and DFS for MCL were 71% and for BDLCL, 31% and 20% respectively. In this preliminary analysis results in MCL are quite good however for patients with DLBCL should be improved. severe toxicity is still present and to date it should be performed only in the setting of well designed clinical trials.

Introduction and Objectives. Lenalidomide is a new inmunomodulatory drug which has shown effectiveness, in combination with dexamethasone, in relapsed or progressive Multiple Myeloma (MM). In our country, little experience outside clinical trials exists since lenalidomide is only currently available in the compassionate use program, for patients with advanced MM. With the purpose of sharing the clinical practical experience with this drug, we considered it interesting to gather the outstanding data on the use of lenalidomide in a multicentric registry, throughout the Spanish scope. We present the preliminary results of this registry.

Background: APL is predominantly associated with low WBC counts. APL with very high WBC counts, i.e. >50 × 109/l, is rare, generally associated with severe coagulopathy and, before the ATRA era, was generally fatal due to early death or subsequent relapse.

Objectives: To identify a clonal population by molecular techniques in patients treated with Fluradabine, Cyclophosphamide, Rituximab (CF+R) and included in the LNF-03 clinical trial. To relate these alterations to the clinical variables at diagnosis and response to treatment. Patients and Methods: Patients: 71 patients from the LNF-03 clinical trial. Their treatment consisted of CF+ Rx6 and posterior maintenance with Rituximab. Peripheral Blood (PB) and Bone Marrow (BM) were studied at diagnosis. Methods: bcl2/IgH rearrangements were studied by real-time PCR (Olsson et al, Mod Pathol 1999). Ig rearrangement of VDJ IgH, Igs IgL KVJ, Kdel and LVJ was studied according to BIOMED II protocols. Results: 43 of the 71 patients (60.56%) presented some molecular alteration in PB or BM. 33% of the patients in the study presented t(14;18) in some of its majority forms, bcl2/IgH mayor 19 (26.4%) and minor 3 (4.22%). 13 patients were positive for bcl-2/IgH, both in BM and in PB. The median amount of blc2/IgH in BM was 8.315% (62.9–0.04), Whereas in pb it was 4.775% (92.6–0.06), with no significant differences observed. Nevertheless, monoclonality was detected in BM in eight cases but not in PB, and to the inverse, one it happened in three patients. Of 71 patients, 38 (53.52%), presented displayed monoclonality in at least one of the Ig genes. Of these patients, 38% presented the clonal rearrangement in IG-L KVJ, 26% in IG-H CDR1, 23% in IG-L KDEL, and 13% rearranged in IG-L LAMBDA. There were 57 patients whose BM was available. 28 of them presented pathological infiltration, and monoclonality was detected in 23 cases; in 29 patients who were not pathologically infiltrated, monoclonality was detected in 12 cases. 83% (6/37) of the patients presented a complete response (CR), 8.1% (3/37) uncertain CR (uCR) and 8.1% (3/37) partial response (PR), after the induction treatment. No relation was found between the presence of molecular alterations in BM/PB and the achievement of a CR. Conclusions: The study of the rearrangements of Ig and bcl2/IgH is a good strategy for identifying lymphomatosus disease at diagnosis; bone marrow is more informative than peripheral blood. The presence of molecular alterations in PB and/or BM is not related to a poorer answer to induction treatment. Partially funded by Roche Farma SA.

Objectives: To identify a clonal population by molecular techniques in patients treated with Fluradabine, Cyclophosphamide, Rituximab (CF+R) and included in the LNF-03 clinical trial. To relate these alterations to the clinical variables at diagnosis and response to treatment.

The routine use of frontline ATRA and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. The incidence and characteristics of late relapses after this combined treatment, however, are not known. Methods: Between 1991 and 1997 (APL 91 and 93 trials) 630 newly diagnosed APL pts received ATRA combined to or followed by DNR-AraC chemotherapy (total of 3 courses), with or without (randomisation) maintenance treatment by continuous 6MP + MTX and/or intermittent ATRA (Blood1993; 82:3241–3249, Blood1999; 94:1192–1200). 582 (92.5%) pts achieved CR. 154 (26.4 %) had a first relapse, after 5 to 120 months. Results: 19 of the first relapses (i.e. 12.3% of the first relapses and 3.2% of pts who achieved CR) occurred more than 4 years after CR achievement (late relapses). Their median age was 45 (range 20–68), and M/F 7/12. Median time to relapse was 72 months (range 50–120). All late relapses involved the bone marrow only. t(15;17) and /or PML-RAR were seen in all cases at relapse. Pts were retreated with ATRA + anthracycline based chemotherapy (CT) (n = 14), ATRA alone (n =2), anthracycline based CT without ATRA (n=1), As2O3 (n =1), ATRA+ As2O3(n =1). 17 of them (89.4%) achieved CR2 and 2 had early death. CR2 pts were allografted (n = 3) autografted (n= 5), received consolidation and maintenance CT +/− ATRA (n = 7), and maintenance ATRA alone (n=2). 14 patients remained in CR2 after 5+ to 78+ months,2 (including 1 of the 2 pts salvaged and maintained with ATRA alone) relapsed after 9 and 22 months and died, and 1 patient developed secondary MDS and died. CR2 was already longer than CR1 in 5 cases. 3 year survival from relapse was 77% (median not reached). By comparison to patients who did not relapse and patients who relapsed < 4 years, patients with late relapse were not different for age and initial platelets. They were more often females and had lower initial WBC counts than patients who relapsed <4 years (M/F=0.54 vs. 2, p=0.01, and mean WBC 7000/mm3 vs. 18000/mm3, p<0.05) but similar to patients who did not relapse (M/F= 0.86 and mean WBC=8100/mm3). Percentages of patients with late relapses having received maintenance treatments (known in APL 93 trial to have reduced the incidence of relapse) were intermediate between those with early relapses and those who did not relapse Conclusion: late relapse was seen in about 3% of APL treated with ATRA and chemotherapy. Initial characteristics of those patients were rather those of “low risk” APL (especially with WBC< 10000/mm3 and female predominance). Their prognosis was overall favourable, in spite of the fact that they generally occurred before As2O3 was available. Combined maintenance with low dose chemotherapy and ATRA during first line treatment may further reduce their incidence, as it does for earlier relapses.

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC.

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC. Methods: We performed a joint analysis of pts < 65 yrs included in studies LPA99 (Spanish PETHEMA) and APL 2000 (French -Belgian-Swiss APL group) to address some of those issues. In LPA99, pts received ATRA combined to Idarubicin (IDA) for induction, followed by 3 consolidation courses, 2 with IDA and 1 with mitoxantrone (MTZ, at cumulative dose of 50 mg/m2), and maintenance with intermittent ATRA and continuous 6MP + MTX during 2 years. Pts with high (WBC > 10000/mm3) and intermediate (WBC < 10000/mm3, platelets < 40000/mm3) Sanz score also received ATRA during consolidation courses and higher cumulative dose of IDA (100 mg/m2), vs low risk pts (no consolidation ATRA, cumulative IDA: 80 mg/m2). No AraC was administered in LPA99 trial. For APL 2000, we restricted the analysis to treatment groups that received AraC: pts with low or intermediate Sanz score received induction with ATRA and DNR (60 mg/m2/d x 3) + AraC (200 mg/m2/d x 7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d x 3) + AraC (1 g/m2/12h x 8) course and the same maintenance as in LPA99. High risk patients received the same treatment, but with intrathecal CNS prophylaxis and, in pts < 60 years, AraC 2g/m2/12h x 8 during the last course. Median follow up was 30 and 22 months in LPA99 (412 pts) and APL 2000 (180 pts), respectively. Comparisons were adjusted on age, gender, WBC and platelet counts. Results: In low and intermediate risk patients (308 LPA99 pts, 97 APL 2000 pts), the CR rates, 2 year cumulative incidence of relapse (CIR), EFS and survival were 96% and 99% (p = 0.2), 2.5% and 6.9% (p = 0.05), 93% and 91% (p = 0.6), 95% and 97% (p = 0.3) in LPA99 and APL 2000 trials, respectively. In high risk patients (104 LPA99 pts, 83 APL 2000 pts), the CR rate, 2 year CIR, EFS and survival were 84% and 95% (p = 0.02), 16.0% and 3.3% (p = 0.06), 69.2% and 88.0% (p = 0.01), 82.4% and 91.2% (p = 0.04) in LPA 99 and APL 2000, respectively. Four relapses in high risk pts involved the CNS in LPA99, vs. none in APL 2000. Three and 5 pts in LPA99 and APL 2000 respectively, died in CR, from treatment toxicity. Conclusion: This analysis suggests than in pts with WBC < 10000/mm3, the current PETHEMA approach yields even fewer relapses than a classical ATRA + DNR + AraC regimen, while being less myelosuppressive. This may be due to the anthracyclines used (IDA and MTZ instead of DNR) and/or to the higher cumulative dose of anthracyclines used in LPA99 trial, and possibly also to consolidation ATRA for intermediate risk pts. On the other hand, in pts with high WBC counts, APL 2000 results yielded better EFS and survival and a strong trend for fewer relapses (including relapses involving the CNS), suggesting a beneficial role for AraC, possibly at high dose, in this subset of patients

The routine use of frontline ATRA and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. The incidence and characteristics of late relapses after this combined treatment, however, are not known.

Myeloablative transplant has been investigated in poor prognosis indolent lymphoma; although recurrence rate is low it is associated with high mortality; the use of non-myeloablative conditioning regimens could reduce TRM maintaining the GVH effect. Up to February 2004, 40 patients with indolent NHL(87% Folicular lymphoma(FL) 5% a lymphocytic well differenciate lymphoma (WDLL) 5% Waldenström Macroglobulinemia(WM) and 3% a Marginal Lymphoma(MZL) have been registered in two prospective multicenter trials;Conditioning regimen consisted of Fludarabine 150 mg and Melphalan 70–140 mg. GVHD prophylaxis consisted of CSA plus short-course MTX. All patients received filgrastim-stimulated peripheral blood stem cells from a HLA related identical donor.Median age at transplant was 50 years (34–67) and 15(40%) had received a previous autologous transplant. At transplant, 5 patients (13%) were in CR1 (after several lines of chemotherapy), 9 (22%) in >CR1, 16 (40%) in PR, 1(2%) had stable disease (after 3 chemotherapy lines) and 9(23%) progressive disease. All patients engrafted. Acute GVHD developed in 22 patients (55%) (18 patients grade II–IV). Chronic GVHD developed in 22 out of 27 patients at risk (81%), being extensive in 13; Disease was evaluated at day +100 and at that moment 22 patients(58%) were in CR, 3 (8%) in PR, two (5%) had stable disease and 11 patients (27%) have died. With a median follow up of 30 months (range: 10–56 months), 24 patients (60%) are alive disease free, 16 (39%) have died, 14 of them (35%) due to transplant toxicity and 2 patients (5%) due to progression. Overall Survival (OS) and Event Free Survival (EFS) are 60 and 58 % respectively. Analysing variables which influence on OS and EFS, patients ≥55 years have a OS significantly shorter than patients < 55 years old (22% vs 66%; p:0,01). Moreover, patients who develop chronic GVHD have an OS and EFS significantly better than those which do not develop it (OS: 89,7 vs 57%; p=0,02 (HR: 9,3-IC95% (2,08–41,5); EFS: 89 vs 42%; p=0,002 (HR: 11,08-IC95% (2,49–49,28)). In conclusion, our results demonstrates the efficacy of non-myeloablative transplant in indolent NHL with a very low relapse rate, indicating the important role of chronic GVHD in the control of the disease; however, mortality rate is still high, mainly in patients ≥55 years

In the present study we have evaluated the outcome of reduced intensity conditioning allogeneic transplant (RIC) in 31 patients with symptomatic B-CLL. 74% of the patients were older than 50 years, and 70% had previously received purine analogues, with 38% of them relapsing or progressing after treatment. At transplant, 83% had active disease. Data from VH homology, FISH analysis, CD38 expression and ZAP 70 expression was available in 21, 27,12 and 2 patients, respectively. 21 out of 31 were conditioned with melphalan plus fludarabine according to our GETH 99–051 protocol; the other patients received other fludarabine-containing regimens. All patients engrafted. Early complete donor chimerism (CDC) (days +28) in Bone Marrow (BM) was observed in 67% of patients; all except two relapsing patients remained CDC after day +180. With a median follow up of 36 months (1–63), 9 patients have died, two of them due to disease progression and seven (22%) due to TRM. In the univariate analysis age older than 55 years, aGVHD and more than two lines of previous chemotherapy significantly influenced TRM (p<0,05). On multivariate analysis only the latter variable remained as an independent prognostic factor (p=0,02).After a median follow up of 36 months (1–63), 9 patients have died, two of them due to disease progression and seven (22%) due to TRM, with a probability for TRM of 26%; Overall survival (OS) and event free survival (EFS) are 64 and 68%, respectively. 23 patients are evaluable for response: CR ( no CD19/CD5/CD23 + cells in BM) was 90% in transplanted patients with active or progressive disease −21 cases−. In 68% of patients, the response was time related to the development of GVHD; with the two latest responses observed at days +240 and +360. Regarding biological characteristics, 12 of the analyzed patients showed unmutated IgVH. The CR rate, EFS and OS of these patients did not differ from that of mutated IgVH patients . In this series 11 patients showed poor prognosis cytogenetics abnormalities (11q- in 7 and 17 p- in 4) and 5 of them had also unmutated IgVH. This group of patients showed a similar outcome to that of patients with normal cytogenetics. CD38 overexpression was detected in 7 out of 10 patients and only one has relapsed. Two patients died due to progression, one was unmutated with normal FISH and the other was 17 p- and CD38+; eight patients had at least two of the above mentioned abnormalities, including 3 with 17p-, and 7 of them, remained in CR between 20 and 63 months. According to this data, a GVL effect associated with GVHD appears to exist in CLL patients receiving RIC allograft Our data demonstrates the efficacy of RIC related allogeneic transplantation in patients with B-CLL and adverse prognostic features. Moreover, our data suggests that CLL could be cured with RIC allograft, avoiding the high TRM of myeloablative regimens.

Myeloablative transplant has been investigated in poor prognosis indolent lymphoma; although recurrence rate is low it is associated with high mortality; the use of non-myeloablative conditioning regimens could reduce TRM maintaining the GVH effect.

In the present study we have evaluated the outcome of reduced intensity conditioning allogeneic transplant (RIC) in 31 patients with symptomatic B-CLL. 74% of the patients were older than 50 years, and 70% had previously received purine analogues, with 38% of them relapsing or progressing after treatment. At transplant, 83% had active disease. Data from VH homology, FISH analysis, CD38 expression and ZAP 70 expression was available in 21, 27,12 and 2 patients, respectively. 21 out of 31 were conditioned with melphalan plus fludarabine according to our GETH 99–051 protocol; the other patients received other fludarabine-containing regimens. All patients engrafted. Early complete donor chimerism (CDC) (days +28) in Bone Marrow (BM) was observed in 67% of patients; all except two relapsing patients remained CDC after day +180. With a median follow up of 36 months (1–63), 9 patients have died, two of them due to disease progression and seven (22%) due to TRM. In the univariate analysis age older than 55 years, aGVHD and more than two lines of previous chemotherapy significantly influenced TRM (p<0,05). On multivariate analysis only the latter variable remained as an independent prognostic factor (p=0,02).After a median follow up of 36 months (1–63), 9 patients have died, two of them due to disease progression and seven (22%) due to TRM, with a probability for TRM of 26%; Overall survival (OS) and event free survival (EFS) are 64 and 68%, respectively.

Sustained complete remissions (CR) have been reached with allogeneic transplant in patients with poor prognosis B-CLL; however, mortality rates are high (20–50%); in order to reduced TRM, NM conditioning are widely used in haematological malignancies; however it is not clear if the use of NM regimens can maintain the efficacy reducing the toxicity. IN this report we performed a retrospective comparison between 30 patients (group A) who have received myeloablative conditioning consisted of TBI plus Cy in 23 pts (74%), TBI, Cy plus VP-16 in 6 pts (19%) and BuCy in 1 patient and 31 patients (Group B) who have received a NM transplant. Conditioning regimens in Group B included: Fludarabine plus Melphalan, 20 pts (64%), Fludarabine, Busulphan and ATG, 5 pts (16%), Fludarabine, TBI and ATG, 4 pts (13%) and Fludarabine plus TBI, 1 patient. All patients received peripheral blood stem cells from a HLA related identical donor. T-cell depletion was performed in 14 patients of the group A. Median age at transplant was significantly higher in the group B patients (53 versus 45, respectively) (p<0,005); no differences were observed in terms of status at transplant and n° of previous chemotherapy lines as well in the risk of graft versus host disease (GVHD) and transplant related mortality (TRM) (See Table, below). With a median follow-up of 71 and 36 months for groups A and B respectively,Overall Survival and Event Free Survival are similar for both groups (53% versus 64% and 60% versus 68%, respectively). Although patients in the NM transplant group were older toxicity was similar in both groups; moreover a similar efficacy has been observed suggesting the clear role of graft versus tumour effect in B-CLL probably more important that the type ofconditining. Table 1 GROUP A Myeloablative Group B Non-myeloablative p Number of previuous chemotherapy lines 2 (1-6) 2 (1-8) NS Acute GVHD 15/30 (48%) 20/31 (64%) NS Grade II-IV 11/30 (35%) 12 /31(38%) NS Chronic GVHD 12/26pts at risk (46%) 18/27 pts at risk (66%) NS Extense 8 pts (30%) 9 pts (33%) NS TRM 7/30 (23%) 7/31 (22%) NS

Sustained complete remissions (CR) have been reached with allogeneic transplant in patients with poor prognosis B-CLL; however, mortality rates are high (20–50%); in order to reduced TRM, NM conditioning are widely used in haematological malignancies; however it is not clear if the use of NM regimens can maintain the efficacy reducing the toxicity. IN this report we performed a retrospective comparison between 30 patients (group A) who have received myeloablative conditioning consisted of TBI plus Cy in 23 pts (74%), TBI, Cy plus VP-16 in 6 pts (19%) and BuCy in 1 patient and 31 patients (Group B) who have received a NM transplant. Conditioning regimens in Group B included: Fludarabine plus Melphalan, 20 pts (64%), Fludarabine, Busulphan and ATG, 5 pts (16%), Fludarabine, TBI and ATG, 4 pts (13%) and Fludarabine plus TBI, 1 patient. All patients received peripheral blood stem cells from a HLA related identical donor. T-cell depletion was performed in 14 patients of the group A. Median age at transplant was significantly higher in the group B patients (53 versus 45, respectively) (p<0,005); no differences were observed in terms of status at transplant and n° of previous chemotherapy lines as well in the risk of graft versus host disease (GVHD) and transplant related mortality (TRM) (See Table, below).