Franco Mandelli

Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma

BACKGROUND High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkins lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment. METHOD A total of 215 patients with relapses of non-Hodgkins lymphoma were treated between July 1987 and June 1994. All patients received two courses of conventional chemotherapy. The 109 patients who had a response to chemotherapy were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55 patients). RESULTS The overall rate of response to conventional chemotherapy was 58 percent; among patients with relapses after chemotherapy, the response rate was 64 percent, and among those with relapses during chemotherapy, the response rate was 21 percent. There were three deaths from toxic effects among the patients in the transplantation group, and none among those in the group receiving chemotherapy without transplantation. The two groups did not differ in terms of prognostic factors. The median follow-up time was 63 months. The response rate was 84 percent after bone marrow transplantation and 44 percent after chemotherapy without transplantation. At five years, the rate of event-free survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation (P = 0.001), and the rate of overall survival was 53 and 32 percent, respectively (P = 0.038). CONCLUSIONS As compared with conventional chemotherapy, treatment with high-dose chemotherapy and autologous bone marrow transplantation increases event-free and overall survival in patients with chemotherapy-sensitive non-Hodgkins lymphoma in relapse.

A Prognostic Score for Advanced Hodgkin's Disease

BACKGROUND Two thirds of patients with advanced Hodgkins disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. METHODS Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkins disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. RESULTS The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. CONCLUSIONS The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkins disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia

BACKGROUND Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission. METHODS After induction treatment with daunorubicin and cytarabine, patients who had a complete remission received a first course of intensive consolidation chemotherapy, combining intermediate-dose cytarabine and amsacrine. Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation; the others were randomly assigned to undergo autologous bone marrow transplantation (with unpurged bone marrow) or a second course of intensive chemotherapy, combining high-dose cytarabine and daunorubicin. Comparisons were made on the basis of the intention to treat. RESULTS A total of 623 patients had a complete remission; 168 were assigned to undergo allogeneic bone marrow transplantation, and 254 were randomly assigned to one of the other two groups. Of these patients, 343 completed the treatment assignment: 144 in the allogeneic-transplantation group, 95 in the autologous-transplantation group, and 104 in the intensive-chemotherapy group. The relapse rate was highest in the intensive-chemotherapy group and lowest in the allogeneic-transplantation group, whereas the mortality rate was highest after allogeneic transplantation and lowest after intensive chemotherapy. The projected rate of disease-free survival at four years was 55 percent for allogeneic transplantation, 48 percent for autologous transplantation, and 30 percent for intensive chemotherapy. However, the overall survival after complete remission was similar in the three groups, since more patients who relapsed after a second course of intensive chemotherapy had a response to subsequent autologous bone marrow transplantation. Other differences were also observed, especially with regard to hematopoietic recovery (it occurred later after autologous transplantation) and the duration of hospitalization (it was longer with bone marrow transplantation). CONCLUSIONS Autologous as well as allogeneic bone marrow transplantation results in better disease-free survival than intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin. Transplantation soon after a relapse or during a second complete remission might also be appropriate.

Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.

BACKGROUND All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. METHODS We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. RESULTS Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. CONCLUSIONS ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

The Threshold for Prophylactic Platelet Transfusions in Adults with Acute Myeloid Leukemia

BACKGROUND Prophylactic platelet transfusions are usually administered to patients receiving myelotoxic chemotherapy when their platelet count falls below 20,000 per cubic millimeter. Some observations suggest that lower platelet counts can be appropriate in patients in stable condition, but the safety of lower thresholds is uncertain. METHODS We evaluated 255 adolescents and adults (age, 16 to 70 years) with newly diagnosed acute myeloid leukemia (but not acute promyelocytic leukemia), who were treated in 21 centers. One hundred thirty-five patients were randomly assigned to receive a transfusion when their platelet count fell below 10,000 per cubic millimeter (or 10,000 to 20,000 per cubic millimeter in those with a temperature above 38 degrees C, with active bleeding, or a need for invasive procedures), and 120 patients were assigned to receive a transfusion when their platelet count was less than 20,000 per cubic millimeter. RESULTS Patients in the group with a threshold of 10,000 platelets per cubic millimeter received 21.5 percent fewer platelet transfusions than the patients in the group with a threshold of 20,000 platelets per cubic millimeter (P=0.001). The numbers of red-cell units transfused were not significantly different between groups. Major bleeding (defined as any bleeding more than petechiae or mucosal or retinal bleeding) occurred in 21.5 and 20 percent of patients, respectively (P=0.41), and on 3.1 and 2.0 percent of the days of hospitalization. One episode of fatal cerebral hemorrhage occurred in the group with a threshold of 10,000 platelets per cubic millimeter; none occurred in the other group (P= 0.95). Actuarial estimates of survival during induction chemotherapy, actuarial estimates of the absence of major bleeding, and the length of hospital stay were not significantly different in the two groups. CONCLUSIONS The risk of major bleeding during induction chemotherapy in adolescents and adults with acute myeloid leukemia (except acute promyelocytic leukemia, which we did not study) was similar with platelet-transfusion thresholds of 20,000 per cubic millimeter and 10,000 per cubic millimeter (or 10,000 to 20,000 per cubic millimeter when body temperature exceeded 38 degrees C, there was active bleeding, or invasive procedures were needed). Use of the lower threshold reduced platelet use by 21.5 percent.

A Controlled-study of Recombinant Human Granulocyte-colony-stimulating Factor in Elderly Patients After Treatment for Acute Myelogenous Leukemia

BACKGROUND Intensive chemotherapy for acute myelogenous leukemia (AML) continues to yield low rates of complete remission and survival among patients over the age of 65 years. Infection-related mortality is particularly high among these patients during the period of neutropenia that follows chemotherapy. We determined the effect of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) on mortality at eight weeks (the main end point) and the rate of complete remission among patients with AML who were 65 years old or older. METHODS After induction chemotherapy with daunorubicin (45 mg per square meter of body-surface area per day for 4 days) and cytarabine arabinoside (200 mg per square meter per day for 7 days), 173 patients with newly diagnosed AML were randomly assigned on day 8 to receive either lenograstim (5 micrograms per kilogram of body weight per day) or placebo, starting on day 9, until there was neutrophil recovery or a treatment failure, or for a maximum of 28 days. Salvage chemotherapy was also followed by lenograstim or placebo. Patients with a complete remission received two consolidation courses of chemotherapy without lenograstim or placebo. RESULTS The mortality rate at eight weeks was similar in the lenograstim and placebo groups (23 and 27 percent, respectively; P = 0.60), as was the incidence of severe infections. The median duration of neutropenia (absolute neutrophil count < or = 1000 per cubic millimeter) was shorter in the lenograstim group (21 days, as compared with 27 days in the placebo group; P < 0.001). Eight percent of the patients in both groups had regrowth of AML cells. The rate of complete remission was significantly higher in the lenograstim group (70 percent, as compared with 47 percent in the placebo group; P = 0.002). Overall survival, however, was similar in the two groups (P = 0.76). CONCLUSIONS The administration of lenograstim after chemotherapy for AML did not decrease the mortality rate at eight weeks among patients over the age of 65 years. The patients who received lenograstim had a significantly higher rate of complete remission than those who received placebo. Nevertheless, the overall survival in the two groups did not differ significantly.

Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) is characterised by a unique fusion transcript, PML/RAR alpha. We tested for this transcript in 35 APL patients who were in apparent remission after various treatments. 11 of 13 patients who tested positive 4 months after achieving remission were in relapse 1-4 months later. All 22 patients who tested negative at 4 months were disease-free after a further 3 months to five years. The test may therefore prove useful in determining the need for additional treatment during clinical remission.

Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph(+) ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10(-3). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10(-3) compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10(-3) at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph(+) ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone.

Reversal of Iron Deficiency Anemia after Helicobacter pylori Eradication in Patients with Asymptomatic Gastritis

Standard care for men and postmenopausal women with iron deficiency anemia is use of gastrointestinal evaluation to exclude gastrointestinal tract abnormality (1, 2). Nevertheless, even when the gastrointestinal tract is investigated thoroughly, a large proportion of patients (around 30%) remain without a diagnosis (2, 3). Recent epidemiologic studies have suggested an association between Helicobacter pylori infection and iron deficiency (4, 5). Infection with H. pylori is recognized as a major risk factor in peptic ulcer disease and gastric cancer, in which lesions are likely to bleed either overtly or in an occult manner, eventually leading to iron deficiency anemia. However, most people infected with H. pylori only have chronic gastritis that is not associated with gastrointestinal bleeding or with any other specific disease (6). It has been suggested that infection with H. pylori may lead to iron deficiency or iron deficiency anemia by impairing iron uptake or increasing iron demand (4). Reversal of iron deficiency anemia after successful eradication of H. pylori was recently observed in children (7, 8) and in a young adult (9). We performed a prospective open study to verify the effects of eradication of H. pylori infection on iron deficiency anemia in patients with H. pylori-associated gastritis. Methods Patients Patients were observed from September 1994 to December 1997. A total of 189 consecutive adult outpatients who were older than 20 years of age and had iron deficiency anemia (158 women and 31 men; median age, 47 years [range, 20 to 79 years]) were referred to our gastroenterology department from the hematology department. Iron-deficiency anemia was defined as a hemoglobin concentration less than 14 g/L for men and less than 12 g/L for women, a mean corpuscular volume less than 80 fL, and a serum ferritin level less than 30 g/L (3). Outpatients with an obvious cause of blood loss, such as a heavy menstrual period (cycles>6 days), epistaxis, active gastrointestinal hemorrhage, or evidence of fecal occult blood positivity, were excluded from the study. Other exclusion criteria were gastrointestinal or hematologic cancer at the time of observation, chronic renal failure, severe cardiopulmonary disease, reported or suspected pica, hemolysis, aplastic anemia or thalassemia, alcoholism or liver cirrhosis, and pregnancy. After this selection, patients who were taking nonsteroidal anti-inflammatory drugs; had had gastric surgery; or had atrophic body gastritis and celiac disease, as described elsewhere (3), were excluded from the study. An iron-poor diet as a cause of iron deficiency anemia was excluded by a hospital dietitian (3). A double-contrast barium enema or colonoscopy plus radiographic examination of the small bowel, or Meckel scintigraphy, were also carried out if indicated. Interventions Patients were treated for 2 weeks with omeprazole, 40 mg, in the morning; amoxicillin, 1g; and metronidazole, 250 mg three times daily after meals, for the first week. Patients were also instructed to discontinue any iron replacement therapy, including over-the-counter iron-containing medication. A clinical evaluation was performed 3 months after eradication therapy to check for clinical signs of anemia. Two follow-up visits at 6 and 12 months were planned. At each visit, a complete blood count was done and ferritin levels were measured. Baseline and 12-month transferrin saturation indexes were also calculated. The 6-month follow-up examination included endoscopy with biopsy to evaluate H. pylori eradication. Patients were considered cured of H. pylori infection if both rapid urease testing and histologic examination of the gastric antral and body biopsy samples were negative. Successful eradication therapy for iron deficiency anemia was defined as no need for iron replacement therapy, recovery from anemia, or both. All patients gave full informed consent to participate the study, which was approved by the local ethical committee. Measurements History of anemia, expressed as length of time from first laboratory diagnosis of iron deficiency anemia to referral to the gastroenterology department, was assessed. Serum ferritin levels were measured by using commercial kits (Ciba-Corning Diagnostic Corp., Milan, Italy) (3). Hemoglobin concentrations and mean corpuscular volume were determined by an automated Coulter counter (Technicon H1, Bayer Corp., Tarrytown, New York) (3). Serum transferrin levels were measured by using a commercial kit (Beckman Analytical, Milan, Italy) (10). Serum iron levels were measured and the transferrin saturation index (normal value, 16% to 45%) was calculated as described elsewhere (10). Patients underwent gastroscopy with gastric antral (n=3) or body (n=3) biopsy. One sample was tested by using a rapid urease test, and the others were examined by conventional histology (3, 9). Duodenal biopsy specimens were also obtained to exclude celiac disease. The pathologist was unaware of clinical and endoscopic data. Gastritis status was described according to the Updated Sydney System classification (8). Helicobacter pylori status was considered positive when the organism was detected on histologic examination, by rapid urease testing, or both. Statistical Analysis Data are expressed as the mean ( SE) or median (range) as appropriate and were analyzed by using the t-test for paired data. Subgroups (percentages of patients) were compared by using the McNemar test. A P value less than 0.05 was considered statistically significant. Role of the Funding Sources Our funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Of the 189 patients referred to our gastroenterology department, 30 (15.9%) had iron deficiency anemia: 4 men and 26 women (of whom 3 were postmenopausal) with a median age of 35.5 years (range, 20 to 65 years). In these patients, H. pylori-associated gastritis was the only pathologic finding. Gastroscopy did not reveal any sign of current or past mucosal erosion or ulcer disease. All patients had a suboptimal response to oral iron therapy; they needed continuous or intermittent oral iron treatment to prevent the decrease of hemoglobin levels. All patients denied having any specific gastrointestinal symptom or having used antisecretory drugs. Occasional, nonpersistent, mild dyspeptic symptoms were considered nonspecific. Anamnestic interview and evaluation of previous medical records documented moderate to severe iron deficiency anemia in all patients (hemoglobin level, 9.5 0.25 g/L; mean corpuscular volume, 69 1.15 fL; and serum ferritin level, 6.2 0.8 g/L) associated with clear clinical signs of anemia, such as fatigue, pallor, and decreased exercise capacity. Median history of anemia and of oral iron therapy in these patients was 4.8 years (range, 2 to 20 years). All patients underwent an eradication regimen. At the 3-month clinical evaluation, no patients reported anemia-related symptoms. Twenty-eight patients underwent endoscopy at 6 months to verify H. pylori eradication. Two female patients (27 and 36 years of age) declined further follow-up because they were in good general health. Helicobacter pylori infection was cured in 25 patients (89.3% [95% CI, 72% to 98%]); at this point, one female 31-year-old patient was excluded from further follow-up because she had developed heavy menstrual periods due to a uterine myoma that was not present at the initial diagnosis. Thus, 24 patients (3 men and 21 women; median age, 35.7 years [range, 20 to 65 years]) in whom H. pylori infection was cured and 3 patients (1 man 21 years of age and 2 women 22 and 37 years of age) in whom H. pylori infection was not cured were eligible for evaluation. Effects of Helicobacter pylori Eradication on Iron Deficiency Anemia At 6 months of follow-up, 18 of 24 (75%) patients recovered from anemia (P<0.001) and had a significant increase in the hemoglobin concentration, mean corpuscular volume, and ferritin level (Table). Table. Hematologic Data from 24 Patients with Iron Deficiency Anemia At 12 months of follow-up, 4 more patients (22 of 24 [91.7%]) showed recovery from anemia without resuming iron supplementation. The mean values of all measurements obtained were similar to those seen at the 6-month evaluation (Table). Even though ferritin levels returned to normal in only 4 patients at the 12-month follow-up visit, we observed a significant increase of more than 300% over baseline values (5.7 0.7 g/L compared with 24.1 5.0 g/L [P=0.0018]; mean increase, 18.4 g/L [CI, 8.08 to 29.44 g/L]). Mean transferrin saturation index also significantly increased from baseline (from 5.5% 0.8% to 18.7% 1.8% [P<0.001]; mean increase, 13.2 percentage points [CI, 8.92 to 17.46 percentage points]), even though values in 5 patients were still below the normal range. Eight patients were followed for 1 more year. Hemoglobin levels returned to normal in the two patients who were still anemic at the previous 12-month examination. In these patients, ferritin levels further increased from those measured at the 12-month follow-up (23.9 6.7 g/L and 30.5 7.4 g/L [P=0.047]; mean increase, 6.6 g/L [CI, 0.5 to 12.6 g/L]). In the three patients who were not cured, the hemoglobin level at 6 months of follow-up was stable in the male patient and was slightly decreased in the two female patients. These three patients experienced mild fatigue. However, in all patients, a clear decrease in ferritin levels was observed (data not shown). Helicobacter pylori Gastritis At diagnosis, 7 patients had mild antral atrophic gastritis, of whom 4 had associated chronic, body nonatrophic gastritis; 1 patient had only body nonatrophic gastritis; and 22 patients had chronic antral nonatrophic gastritis, 20 of whom had a similar pattern in the gastric body mucosa. Thus, considering the involvement of both gastric compartments, 24 of 30 (80%) patients with iron de

Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients.

The prognostic value of 12 clinical and haematological parameters, recorded at diagnosis, in myelofibrosis with myeloid metaplasia (MMM) was retrospectively analysed in a consecutive series of 133 patients followed for a minimum of 60 months. Multivariate analysis showed that the following features were associated with a significantly shorter survival: (1) short period of time (<13 months) between first symptoms and diagnosis; (2) anaemia (haemoglobin <10 g/dl); (3) leucocyte count >12 × 109/l; (4) peripheral blood granulocyte precursors >10%. Age, splenectomy and percentage of peripheral blood metamyelocytes were found significantly to affect survival only from univariate analysis, whereas sex, size of spleen, thrombocytopenia and thrombocytosis were of no prognostic significance. These data suggest that a more intensive chemotherapy might be useful for younger patients with bad prognostic factors at diagnosis.