High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.

The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.

Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy.

Several studies have reported a higher prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (NHL) than in the general population. Treatment for NHL includes the use of chemotherapeutic agents such as cytotoxic drugs, corticosteroids, and rituximab, which can be immunosuppressive and hepatotoxic. While reactivation of hepatitis B virus (HBV) when undergoing immunosuppressive therapy for haematological malignancies is a well-documented complication, data on HCV reactivation or liver function impairment after chemotherapy for NHL are controversial. From January 2006 to December 2009, 207 consecutive NHL patients treated with chemotherapy without rituximab (CHOP) or with rituximab (R-CHOP) were observed; screening for HCV infection and baseline liver function tests were performed in all patients. The prevalence of HCV infection was 9.2%. This prevalence is higher than that observed in the general population in Italy (3%). Among the HCV-infected subjects, the incidence of hepatitis flares was 26.3% vs 2.1% among the HCV-uninfected individuals. Although less frequent and less severe than in HBV-infected subjects, liver dysfunction can occur as a consequence of rituximab-containing regimens in HCV-infected patients with NHL. In the cases considered in this study, no patient treated with chemotherapy without rituximab developed hepatitis flares. The frequency and the severity of this complication vary in different reports. Therefore, we recommend the assessment of liver function and the screening of all patients with NHL for HCV infection before starting chemotherapy; we also recommend monitoring of liver function tests and HCV-RNA serum levels during treatment.

Trigeminal neuralgia as unusual isolated symptom of fungal paranasal sinusitis in patients with haematological malignancies.

A sinonasal infection is a frequent complication in patients with haematological malignancies, and may represent a challenge in terms of differential diagnosis between a bacterial or fungal infective process and tumour localization. A timely and correct diagnosis in these patients is critical and, therefore, may require consultation of specialists outside of haematology; an incorrect diagnosis which underestimates the seriousness of the infection can be fatal. Symptomatic trigeminal neuralgia resulting from direct compression or perineural invasion from malignancy is not uncommon in the literature. However, trigeminal neuralgia as an isolated symptom at the onset of a bacterial or invasive fungal sinusitis is rare and risks going unnoticed. The authors herein describe three cases of patients affected by acute myeloid leukaemia or lymphoma in which an invasive fungal sinusitis appeared at the onset as an isolated trigeminal neuralgia, with pain located along the distribution area of the second branch of the trigeminal nerve. Only after referring these patients to a neurologist for a host of neurological exams it was possible to confirm a diagnosis of secondary maxillary sinus fungal involvement.

Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features.

Although the occurrence of thrombosis in acute promyelocytic leukemia (APL) has been reported during retinoic acid treatment, no studies carried out in large clinical cohorts have specifically addressed this issue. We analyzed 124 APL patients treated with the all-trans retinoic acid and idarubicin protocol and compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 patients who had no thrombosis. In seven patients, the events were recorded during induction, whereas in four patients deep vein thrombosis occurred in the post-induction phase. Comparison of clinico-biological characteristics of patients with and without thrombosis revealed in the former group higher median white blood cell (WBC) count (17 x 10(9)/l, range 1.2-56, P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3-ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correlation was found with sex, age, French-American-British subtype, all-trans-retinoic acid syndrome or with thrombophilic state that was investigated in 5/11 patients. Our findings suggest that, in APL patients consistent biologic features of leukemia cells may predict increased risk of developing thrombosis.

Diffuse large B-cell lymphoma involving the breast. A report of four cases.

Non-Hodgkin lymphoma of the breast is an uncommon form of lymphoma occurring either primary disease (PBL) or part of systemic involvement. We report the clinical outcome of 4 consecutive cases with CD20+ diffuse large B-cell lymphoma (DLBCL) of the breast, in the attempt to further clarify the management of this disease. The median age was 53 years (39-61), stages were IIE (n=2), IIIE (n=1), and IV (n=1); IPI scores were 0 (n=2), 2 (n=2). Two cases were PBL, and 2 were secondary involvement of the breast. Two stage IIE patients received MACOP-B, radiation therapy was given to one of them and both achieved CR. The stage IIIE patient treated with MACOP-B plus Rituximab was in PR at the beginning of the Rituximab and achieved CR at the end of the treatment. The 61-year-old stage IV patient and bilateral involvement received P-VNBEC as first line treatment, achieving PR; she was then treated with 4 cycles of MACOP-B plus Rituximab obtaining CR. After a median follow-up of 40 months (31-50) all patients are alive and in CR. No CNS prophylaxis was given and no incidence of CNS relapse was observed. In our experience DLBCL of the breast shows chemosensitivity to MA-COP-B regimen but the intensification with Rituximab seems to be effective especially in the advanced stages. Further and comparative studies are required to confirm the validity of our results.

Southern blot analysis of ALL-1 rearrangements at chromosome 11q23 in acute leukemia.

The chromosome 11q23 band is a genetic region frequently involved in nonrandom karyotypic abnormalities of acute leukemia. A genomic locus named ALL-1 or MLL, where 11q23 breakpoints are clustered, has been recently cloned and characterized. We have made use of an ALL-1-specific probe in Southern blot experiments to analyze the configuration of this gene in a large series of acute leukemia patients, representative of all different myeloid and lymphoid subtypes. Nine of 145 cases (6.2%) showed abnormal ALL-1 restriction fragments in leukemic DNAs. Of these nine cases, five patients in whom karyotypic data were available displayed chromosome 11q23 aberrations, including t(4;11) (three cases) and t(9;11) (two cases). Immunophenotypic and morphocytochemical characterization of ALL-1-rearranged acute leukemia revealed prevalence of poorly differentiated B lymphoid and/or monoblastic features. Considering the whole series, ALL-1 rearrangements were significantly associated with female sex, higher white blood cell counts at presentation, and very poor clinical outcome. The presence of residual disease was molecularly documented in one case at the time of clinical remission after induction treatment and was followed by early relapse. We conclude that ALL-1 rearrangements are new molecular markers of human leukemia with considerable diagnostic and prognostic relevance.

Sequential combination of systemic high-dose ara-C and asparaginase for the treatment of central nervous system leukemia and lymphoma.

Eight patients with overt central nervous system (CNS) leukemia and lymphoma were treated with sequential administration of systemic high-dose cytosine arabinoside (HiDAC) and asparaginase (ASP) with no direct CNS therapy. Complete clearing of the cerebrospinal fluid (CSF) was achieved in six (86%) of seven patients with meningeal disease, generally after the first course of therapy. Two patients presented with evidence of extensive intracerebral disease; both responded with a greater than 50% regression of the tumor infiltrates. Concomitant extraneurologic localizations responded equally well to HiDAC/ASP: responses were seen in four of five patients, including complete remission in three of four patients who presented with marrow involvement. Toxicity was generally moderate and limited to myelosuppression (eight of eight patients), tolerable nausea and vomiting (eight of eight patients), mild hepatotoxicity (two of eight patients), and oral mucositis (one of eight patients). These results indicate that HiDAC/ASP is a tolerable and highly effective treatment modality for CNS leukemia and lymphoma and suggest its potential role for sanctuary chemoprophylaxis.

Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group.

PURPOSE: To assess the value of granulocyte-macrophage colony-stimulating factor (GM-CSF) for induction treatment of acute myeloid leukemia (AML), both for priming of leukemic cells and for acceleration of hematopoietic recovery. PATIENTS AND METHODS: GM-CSF was administered 5 micrograms/kg/d by continuous intravenous (i.v.) infusion during induction therapy with daunorubicin (DNR) (days 1 to 3) and cytarabine (ARA-C) (days 1 to 7). A total of 102 patients were randomized onto four arms, as follows: (1) GM-CSF 24 hours before and during chemotherapy (arm +/-); (2) GM-CSF after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes (PMNs) (arm -/+);(3) GM-CSF before, during, and after chemotherapy (arm +/+); or (4) no GM-CSF (arm -/-). Stopping rules were applied in case of an initial WBC count greater than 30 x 10(9)/L or a secondary increase of circulating blast cells. Analyses were performed according to the intention-to-treat principle. RESULTS: The complete remission (CR) rates were 77% (arm -/-), 72% (arm +/-), 48% (arm -/+), and 46% (arm +/+). Patients randomized to receive GM-CSF after induction (arms -/+ and +/+) had a significantly lower CR rate (P = .008) and a trend toward accelerated recovery of neutrophils, but no fewer infections or induction deaths. The lower CR rate appeared to be related to an increased resistance rate, with persistent leukemia. The main side effects of GM-CSF were fluid retention and hypotension. CONCLUSION: GM-CSF administered during induction treatment of AML with a DNR/Ara-C combination did not provide any clinical benefit. Furthermore, there was a significant decrease in the CR rate with more persistent leukemia when GM-CSF was administered during the hypoplastic phase after the chemotherapy courses.

Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia.

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.

Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography.

PURPOSE: Neutropenic enterocolitis (NE) is a severe complication of intensive chemotherapy and is barely identifiable by clinical signs alone. Ultrasonography (US) supports the diagnosis of NE by showing pathologic thickening of the bowel wall. The aim of this study was to evaluate the prognostic value of the degree of mural thickening evaluated by US in patients with clinically suspected NE. PATIENTS AND METHODS: Neutropenic patients with fever, diarrhea, and abdominal pain after intensive chemotherapy for hematologic malignancies were studied with abdominal US. We evaluated the degree of bowel wall thickening detected by US and its correlation with the duration of the clinical syndrome as well as NE-related mortality. RESULTS: Eighty-eight (6%) of 1,450 consecutive patients treated for leukemia had clinical signs of NE. In 44 (50%) of 88 patients, US revealed pathologic wall thickening (mean +/- SD, 10.2 +/- 2.9 mm; range, 6 to 18). The mean duration of symptoms was significantly longer in this group (7.9 days) than among patients without mural thickening (3.8 days, P <.0001), and the NE-related mortality rate was higher (29.5% v 0%, P <.001). Patients with bowel wall thickness of more than 10 mm had a significantly higher mortality rate (60%) than did those with bowel wall thickness < or = 10 mm (4.2%, P <.001). CONCLUSION: Symptomatic patients with sonographically detected bowel wall thickening have a poor prognosis compared with patients without this finding. In addition, mural thickness of more than 10 mm is associated with poorer outcome among patients with NE.

In vitro and in vivo effects of 5-aza-2'-deoxycytidine (Decitabine) on clonogenic cells from acute myeloid leukemia patients.

5-Aza-2'-deoxycytidine (Decitabine) is an analog of deoxycytidine now entering clinical trials in acute myeloid leukemia (AML) owing to a defined antileukemic activity mediated at least in part by DNA hypomethylation, altered gene expression, and induction of cell differentiation. In the present study, we examined the relationship between the in vitro sensitivity to Decitabine of blast progenitors and the clinical outcome, in nine AML patients treated in vivo with Decitabine within a phase II trial carried out at two different institutions. Leukemic blast progenitors in acute myeloid leukemia (AML) undergo terminal divisions giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected by a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. Three out of four patients, in which clonogenic cells in methylcellulose were strongly suppressed by Decitabine and clonogenic growth of blasts cultured in suspension was only slightly affected, failed on Decitabine treatment in vivo. Two subjects, whose blast progenitors in suspension culture were significantly inhibited by Decitabine, obtained a positive hematological response (complete or partial remission, CR or PR) and an additional patient showing a similar in vitro pattern died in induction with an hypoplastic marrow without morphological evidence of persistant leukemia. Interestingly two patients displaying an unfavourable in vitro pattern (i.e. a minor suppression of self-renewal mitoses as evinced from suspension cultures) achieved a hematological response (CR and PR) upon in vivo therapy with Decitabine. The in vitro response to Decitabine of clonogenic progenitors from both these patients shifted to a favourable pattern (i.e. major suppression of self-renewal versus terminal mitoses) following manipulation of culture conditions by the addition or removal of exogenous growth factors. In addition, in a further patient refractory to treatment with Decitabine in vivo, similar alterations of the culture conditions were unable to modify the unfavourable pattern of response to the drug in vitro. Our results indicate that the sensitivity of blast progenitors in suspension cultures strongly correlates with the remission outcome of the patients. From our data, it also appears that alterations of culture microenvironment are able to modify the response of AML blasts to Decitabine, unveiling the 'hidden' sensitivity of leukemic progenitors to the drug in cases characterized by a discrepancy between in vivo and in vitro results, i.e. apparent in vitro resistance and favourable clinical outcome.

A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia.

Thirty-one patients with either advanced AML (18) or blastic CML (13) were treated with an intensive timed sequential combination of VP-16 (100 mg/m2/day i.v., days 1-3 and 8-10), intermediate-dose Ara-C (500 mg/m2 i.v. over 1 h q 12 h, days 1-3 and 8-10) and carboplatin (150 mg/m2/day i.v. continuous infusion, days 1-3 and 8-10). CR rates were 9/18 (50%) for patients with AML and 9/13 (69%) for those with blastic CML, for an overall CR rate of 58%. Among patients with AML, CR rates for specific subgroups were: primary resistant disease 2/6; resistant relapse 1/5; second relapse 6/7. Ten patients were refractory to VAC and three (10%) died of complications during marrow hypoplasia. Median overall survival was 7 months, and median DFS of the 18 responders 4 months. The major toxicity was myelosuppression and infection. The VAC regimen has significant activity and acceptable toxicity in myelogenous leukemias. The very high response rate observed in blastic CML warrants further testing of carboplatin-based regimens in this poor-risk form of leukemia.

Phase II trial of intermediate dose ARA-C (IDAC) with sequential mitoxantrone (MITOX) in acute myelogenous leukemia.

Forty-seven patients with primary refractory, relapsed, and previously untreated, poor risk AML were entered into a phase II study of intermediate dose ARA-C (IDAC) (1 g/m2 i.v. over 6 hr, daily for 6 days) with sequential mitoxantrone (MITOX) (6 mg/m2 i.v. bolus 3 hr after the end of each ARA-C infusion). Overall, complete remission was induced in 31 patients (66%), and 1 additional patient entered a partial remission. Seven patients (15%) died of infection during marrow hypoplasia. Response to IDAC + MITOX was influenced by sensitivity to previous therapy: patients with primary refractory and early relapse AML responded less well to the regimen (CR rate 28% and 33%, respectively), as compared to those with previously untreated (CR rate 64%) or late relapse disease (CR rate 85%). Sixteen patients continue in CR at 1-12+ months. Except for the expected severe myelosuppression, the regimen was well tolerated with minimal extramedullary toxicity. The data indicate that the sequential combination of IDAC and MITOX is an effective and tolerable regimen for AML. Consideration should be given to applying this program at earlier stages of AML therapy.

Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results.

5-Aza-2'-deoxycytidine (Decitabine) is a new cytosine analog with potent antileukemic activity and able to induce in vitro gene activation and cellular differentiation by a mechanism probably involving DNA hypomethylation. The aim of this pilot study was to evaluate the efficacy and the toxicity of Decitabine, used as single induction agent, in the treatment of poor prognosis acute myeloid leukemia (AML) patients, and to explore its mechanism of action. A total of 12 patients were treated with Decitabine at 90-120 mg/m2 as a four hour intravenous infusion, three times daily for three consecutive days every four to six weeks. A minimum of two courses were required for response evaluation and to consider a patient as therapeutic failure. A total of 10/12 patients were fully evaluable for response; three patients achieved a complete remission (CR) and one a partial remission (PR). Extra-hematological toxicity was generally mild. As for the mechanism of action, both a differentiation induction effect and a cytotoxic mechanism have been observed. In particular, CRs and PRs were probably obtained through the induction of leukemia cell differentiation as shown by the kinetic of remission and immunotyping studies. The preliminary results of this ongoing study suggest that Decitabine may have a prominent role in the treatment of those AML patients with poor general conditions and/or advanced age.

Polycythemia vera treated with pipobroman as single agent: low incidence of secondary leukemia in a cohort of patients observed during 20 years (1971-1991).

The 'gold standard' for the treatment of polycythemia vera (PV) is to date undefined. We performed a retrospective analysis to evaluate the outcome of a cohort of PV patients treated with pipobroman (PB) at a single institution during a period of 20 years (November 1971-October 1991). During this period, a total of 366 adult PV patients were diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of these, only 199 (54%) were treated with PB: 92 were males and 107 females, median age was 63.0 years (range 25.2-87.3 years). Major clinical characteristics at onset were as follows: 34 (17%) patients had splenomegaly >3 cm below costal margin, 70 (35%) had platelets >600,000/mm3, 79 (40%) had white blood cells >12,000 mm3; 97 (49%) had hypertension, 83 (42%) had minor neurological symptoms (as vertigo, headache, paresthesias), 33 (17%) had pruritus and 27 (13%) had thrombotic features. All patients received PB at the dosage of 1 mg/kg/day until response was achieved (hematocrit value <50% in males and <45% in females). Thereafter treatment was given according to toxicity and maintenance of response. All patients were phlebotomized before starting treatment (mean number of phlebotomies performed: three, range 2-4) and 47 of them received PB when hematocrit value was already reduced at response levels: therefore, while all patients are evaluable for acute and long-term toxicity, only 152/199 (76.4%) patients are evaluable for response to PB. During a median time of 2 months, all these 152 patients achieved the response; as maintenance, 128/199 (64.3%) patients were managed with PB alone and 71/199 (35.7%) patients received phlebotomies occasionally. Sixty-one out of 199 (30.6%) patients developed disease-related complications (25 neurological symptoms, 21 thrombotic complications, 12 cardiovascular problems, three hepatic failures). Eleven (5.5%) patients developed acute myelogenous leukemia (AML) after a median time of treatment of 89 months (range 33-188 months), 11 (5.5%) patients developed myelofibrosis (median time from treatment 71 months, range 31-182 months) and in six (3%) patients cancer occurred (median time from treatment 85 months, range 13-118 months). The cumulative risk of leukemia in PV was 2% (95% CI: 0-4%) and 6% (95% CI: 1-11%) at 5 and 10 years respectively; the cumulative risk of myelofibrosis was 2% (95% CI: 1-5%) and 9% (95% CI: 3-15%) at 5 and 10 years, respectively. As of May 1996, 33 (16.6%) patients are lost to follow-up, 40 (20.1%) are dead and 126 (63.3%) are alive with a median overall survival of 191 months. In conclusion, this retrospective analysis confirms the efficacy and safety of PB in PV patients and its low leukemogenic role; prospective studies are needed to evaluate the real impact of PB in the treatment of PV.

In vitro purging with BCR-ABL antisense oligodeoxynucleotides does not prevent haematologic reconstitution after autologous bone marrow transplantation.

We treated a patient with chronic myeloid leukaemia in accelerated phase with autologous bone marrow transplantation. Before reinfusion, cells were purged in vitro with a 26-mer phosphorothioate antisense oligodeoxynucleotide specific for the B2A2 junction. Incubation with antisense oligodeoxynucleotides produced a 24 and 41% reduction of CFU-GM and CD34+ cells, respectively. However, an in vitro test previously performed as a screening for patient inclusion in this procedure, revealed a 38 and 75% reduction of colony formation after 24-h and 168-h incubation, respectively. The patient showed bone marrow engraftment 15 days after reinfusion and haematological reconstitution after 17 and 25 days for platelets and neutrophils, respectively. Using fluorescence in situ hybridization in interphase nuclei, we demonstrated the presence of a proportion of Ph-negative cells in repeated controls after the autograft. The patient is now in unmaintained complete haematological remission 9 months after the autograft.

In vivo effect of granulocyte-macrophage colony-stimulating factor on the kinetics of human acute myeloid leukemia cells.

Granulocyte-macrophage colony-stimulating factor, (GM-CSF) was given at 8 micrograms/kg daily by continuous i.v. infusion for 72 h to six patients with acute myeloid leukemia (AML) in expansion and one with chronic myeloid leukemia in blastic crisis to determine whether it was possible to augment the proliferative activity of the neoplastic population. The percentage of marrow blasts in S phase (labeling index, LI) was increased in five patients (1.3-, 1.5-, 1.9-, 2.3- and 3.2-fold change). The increase in LI was similar 24 and 48 h after beginning GM-CSF. The RNA Index also increased in patients who showed an increased LI, suggesting that GM-CSF had recruited quiescent neoplastic cells into the cell cycle. Forty eight hours after beginning GM-CSF, chemotherapy was started. The fate of S phase cells, labeled in vivo with bromodeoxyuridine (BrdU) immediately before cytostatic treatment, was monitored. BrdU positive cells were identified by fluorescent antibody for up to 28 days. A preferential killing of BrdU (S phase) cells was observed in 5/7 patients who obtained a complete remission, whereas this was not apparent in the two patients who achieved only a partial remission. Chemotherapy induced a rapid and profound aplasia; its duration, however, was not significantly different from that observed in historical controls. GM-CSF may have a potential role in the treatment of AML, as this study shows that it recruits leukemic cells into the cell cycle without adversely prolonging aplasia after cycle-specific therapy.

Serum interleukin-2 (IL-2), soluble IL-2 receptors and tumor necrosis factor-alfa levels are significantly increased in acute myeloid leukemia patients.

Serum interleukin-2 (IL-2), soluble IL-2 receptors (sIL-2R) and tumor necrosis factor-alfa (TNF-alpha) levels were determined in 66 previously untreated consecutive patients with acute myeloid leukemia (AML) and in 22 normal volunteers. The following mean (+/- SE) values were observed in patients and controls, respectively: 35 +/- 14.7 (range 0.5-500) and 0.7 +/- 0.02 (0.5-0.8 U/ml for IL-2 (p = 0.001); 1622 +/- 289 (110-10,600) and 422 +/- 30 (207-666) U/ml for sIL-2R (p = 0.0001); 1247 +/- 196 (218-4672) and 152 +/- 11 (75-308) pg/ml for TNF-alpha (p = 0.0001). With respect to the FAB classification system, we found a significantly different distribution of serum IL-2 mean values in distinct subcategories, i.e. 3.4 +/- 1.9 U/ml in M1-M2-M3 and 42.4 +/- 20.4 U/ml in M4-M5 subgroups, respectively (p = 0.01), whereas sIL-2R and TNF-alpha levels were 1144 +/- 322 U/ml and 1120 +/- 317 pg/ml in M1-M2-M3 patients and 1945 +/- 317 U/ml and 1270 +/- 259 pg/ml in the M4-M5 group. A significantly positive correlation between TNF-alpha and sIL-2R (r = 0.53; p = 0.002) was also detected in the M4-M5 group. Sixty-three out of 66 patients received an intensive chemotherapy program. Univariate analysis showed that age and sIL-2R greater than 2000 U/ml significantly affected both complete remission rate and overall survival, whereas by multivariate analysis, age was the only independent variable significantly influencing survival. These data confirm recent in vitro evidence suggesting the role of IL-2, sIL-2R, and TNF-alpha in the control of normal hematopoiesis and leukemogenesis. Since the availability of recombinant cytokines for clinical use in AML, it is crucial to understand their spectrum of interaction in order to select the appropriate combination for in vivo administration.

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia.

A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.

Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.