Risk factors for severe infection in patients with hairy cell leukemia: a long-term study of 73 patients.

Although the survival of patients with hairy cell leukemia (HCL) has been improved by the therapeutic introduction of interferon alpha and purine analogs, it is still worsened by complications such as severe infections. In this long-term study, we identified factors influencing patient outcomes in 73 patients with HCL. Median age at diagnosis was 53 yr and the gender ratio (M/F) was 2.3. At the time of HCL diagnosis, 60 patients (82%) were symptomatic and 22 of these had an infection. After a median follow-up of 13 yr, eight patients had died of secondary cancer (n = 2), HCL progression (n = 1) and age-related complications (n = 5). The 10-yr overall survival (OS), progression-free survival and relapse rates were 91 +/- 3%, 14 +/- 5% and 87 +/- 5%, respectively. In multivariate analyses, age >53 yr was the only factor adversely influencing OS and secondary cancer incidence, with adjusted hazard ratio (HR) of 9.30 (95%CI, 1.15-76.6; P = 0.037) and 2.80 (95%CI, 1.05-7.71; P = 0.04), respectively. Eleven patients developed severe infections. Absolute lymphocyte count (<1 x 10(9)/L) at diagnosis was the only factor influencing the occurrence of severe infections, with an adjusted HR of 4.01 (P = 0.007). Strikingly, we did not observe any significant correlation between neutrophil or monocyte counts and the incidence of infection. We confirmed long-term survival in HCL but found a high incidence of infection - even late in the course of the disease. The absolute lymphocyte count at diagnosis is a risk factor for the occurrence of severe infections. In addition to careful monitoring of infections, prompt initiation of anti-HCL treatment should be considered in patients with low lymphocyte counts.

Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I.

The current most powerful prognostic model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the ISS stage I (high albumin and low b2m) may vary. Ki-67 is a nuclear protein associated with cell proliferation. We retrospectively evaluated the percentage of bone marrow plasma cells expressing Ki-67 antigen (Ki-67 index) in a series of 174 untreated MM patients at diagnosis. Median survival was 51, 41 and 20 months respectively, and median Ki-67 index was 3.0%, 6.1% and 6.5% in ISS stages I, II, and III respectively. Independently of ISS, Ki-67 index > or =4% was highly predictive of adverse prognosis. Ki-67 index correlated with markers of intrinsic malignancy and with markers of tumour burden. Within ISS stage I, median survival was of 31 months (RR of death 2.65) in patients with Ki-67 index > or =4%. Eventually, the combination of Ki-67 with b2m produced an efficient prognostic model, which appeared most effective in our series when compared with b2m and KI-67 with chromosome 13 deletion models. In this series, we demonstrated that a proliferation marker provides clear-cut additional survival prognostic information to b2m into the ISS model.

Quantification by magnetic resonance imaging and liver consequences of post-transfusional iron overload alone in long term survivors after allogeneic hematopoietic stem cell transplantation (HSCT).

We quantified and studied the impact of post transfusional iron overload alone in post allogeneic HSCT. Median number of RBCs was 18. Ferritin was 532 mg/L. Liver iron content (LIC) was 117 mmoles/gdw. Correlation RBCs and ferritin was (r=0.81); RBCs and LIC was (r=0.84). The high ferritin group differed from normal ferritin group in terms of RBCs transfused (p<10(-3)), ALT (p<0.009). But occurrence of liver dysfunction was not significant. Magnitude of iron overload correlates closely to the number of RBCs and is quantified by MRI. Impact on liver dysfunction is moderate in absence of co-morbidity.

Enteral feeding and early outcomes of patients undergoing allogeneic stem cell transplantation following myeloablative conditioning.

The purpose of this study was to evaluate the impact of enteral nutrition on early outcome of patients after myeloablative allogeneic stem cell transplantation (allo-SCT). From January 2001 to January 2003, 22 patients agreed to receive enteral nutrition via a nasogastric feeding tube; the remaining 23 patients received parenteral nutrition (n=22) or standard oral feeding (n=1). Early complications and factors influencing 100-day overall survival (OS) were investigated. Patients who received enteral nutrition developed less often acute-grade III/IV graft-versus-host disease (18%) than those who did not (35%) (P=0.011). In addition, this group showed lower mortality from infection during the first 100 days after transplantation. In multivariate analyses, only the absence of enteral nutrition was found to adversely influence 100-day OS with a hazard ratio of 8.3. Enteral nutrition is a safe and effective method for feeding allo-SCT patients. A randomized trial is warranted to confirm its advantage on early patient outcome.

An 18-case outbreak of drug-resistant Pseudomonas aeruginosa bacteriemia in hematology patients.

We retrospectively identified an outbreak of 18 episodes of P. aeruginosa bacteriemia in 17 patients with hematologic malignancies in 2004. All strains were ticarcillin I/R, 77% ciprofloxacin I/R, 72% ceftazidime I/R, 72% amikacin I/R and 50% imipenem I/R. The outbreak was multiclonal. Colistin was employed for documented therapy in ten cases including seven in which it was the only active drug. Outcomes were resolution of infection in 12 out of 18 episodes (67%), and death in six cases, five (25%) of which were attributable to the infection. Colistin was useful even in highly resistant strains and the efficacy of antibacterial therapy was similar (57%)in bacteriemia due to strains only susceptible to colistin.

Long-term outcome in acquired aplastic anemia treated with an intensified dose schedule of horse antilymphocyte globulin in combination with androgens.

Aplastic anemia (AA) is a rare hematopoietic stem cell disease, which can be treated with horse antilymphocyte globulin (ALG) for patients not eligible for bone marrow transplantation. ALG gives about 60% overall survival rate (OS) after 5 years, a 30% of persistent complete remission and a 20% early death rate related to failure. ALG has been incriminated in the emergence of 10 to 20% therapy-related AML/MDS (t-AML/MDS) with the usual doses. Questions remain whether higher doses of ALG could improve the response and OS rates and whether the combination with androgens is able to protect patients from t-AML/MDS. We have carried out a single institutional retrospective study of 87 AA treated with higher doses of ALG, twice the usual posology (140 mg/kg instead of 75 mg/kg), combined to androgens. The overall response rate was 77% and the OS rate at 5 years was 78%. Androgens in combination with ALG improved response and OS rates. At diagnosis, 6% of AA had an abnormal karyotype using conventional cytogenetic not related to any time-to-event. Two patients displayed a cytogenetic conversion related to the occurrence of secondary malignancies. The incidence of t-AML/MDS was 2.3% with an estimated 10-year cumulative incidence of 3.1. Our results show that higher doses of ALG combined to androgens are feasible and give results close to those recently describe with the immunosuppressive treatments including ALG associated to cyclosporine, with a low SMD/AML incidence rate.

[Indications of G-CSF administration in hematologic disorders]. / Indications des facteurs de croissance granulocytaires en hématologie.

Granulocyte colony stimulating factors (G-CSF) are largely used in the treatment of hematologic disorders to improve both the myelosuppression which might directly result from the disease or indirectly induced by the numerous chemotherapy regimen. G-CSF reduces the depth and duration of neutropenia in lymphoma patients and thus allows the design of more dose intense chemotherapy regimen which were shown to improve outcome particularly in patients with diffuse large B-cell and Hodgkin's lymphoma. G-CSF has been studied in patients with acute leukemias (ALL and AML) both concomitantly to induction chemotherapy to sensitize leukemic cells and after chemotherapy to reduce the duration of neutropenia and incidence of severe infection but it's benefit in these settings is still controversial. Myelodysplastic syndromes (MDS) can benefit from G-CSF in association with erythropoietin, particularly for patients with relative good prognosis according to the IPSS score at diagnosis. Still, an improvement of Quality of life needs to be demonstrated in the vue of the cost of these strategies. In aplastic anemia (AA), G-CSF has been used as a support during infection or in association with immunosuppressive treatments but caution is needed regarding the risk of clonal evolution in AA. The benefit of low dose G-CSF in chronic severe neutropenia is well established but the long term consequences of continuous G-CSF support are not known. Finally, G-CSF given alone or after chemotherapy as become one of the key components of hematopoietic stem cell mobilization allowing the use of high dose therapies with autologous or allogeneic stem cell support.

High-risk pregnancies in Diamond-Blackfan anemia: a survey of 64 pregnancies from the French and German registries.

We reviewed 64 pregnancies in 26 women with Diamond-Blackfan anemia (DBA) included in the French and German DBA registries. Complications were seen in 42 pregnancies (66%) and included abortion, pre-eclampsia, in utero fetal death, intrauterine growth retardation, retroplacental hematoma, pre-term delivery and fetal malformations. Of the 34 children (53%) born alive, 13 had DBA. No correlations were found between pregnancy outcome and features of either maternal or child DBA. Pregnancies in DBA-affected women are at high risk, especially for complications likely to be of vascular-placental origin. Careful monitoring with prevention of severe anemia and early introduction of aspirin is suggested.

Cryptic 6p21.3 duplications and triplication involving HMGA1 partially masked by add 6p in four cases of myelodysplasia.

Rearrangements of 6p are frequent in both myeloid and lymphoid malignant hematological disorders. High-mobility group AT-hook 2 (HMGA2) rearrangements have been described in myelofibrosis with myeloid metaplasia (MMM) and also in myelodysplasia. High-mobility group A proteins are nonhistone nuclear proteins that bind DNA and regulate the transcriptional activity of many genes. We used FISH, with bacterial artificial chromosome RP11-513I15 probe, to study 16 cases of myeloid malignancies with chromosome 6 short arm rearrangements, most of them following myeloproliferative disorders. Among these we found two 6p21.3 duplications and one 6p21.3 triplication involving HMGA1 in four cases of myelodysplasia with and without myelofibrosis. In these four cases, duplications and triplication were partially masked at the cytogenetic level by a derivative chromosome 6 resulting from translocation with another chromosome. HMGA1 proteins have been recently found overexpressed in human leukemias, but to our knowledge this is the first reported duplication of HMGA1.

Outcome of patients less than 55 years of age with high-risk acute leukemia who did not have an human leukocyte antigen-identical related donor: a long-term study of 97 consecutive patients.

Between January 1993 and December 2000, an unrelated donor search (UDS) was initiated for 97 consecutive patients [46 acute lymphoblastic leukemia (ALL) and 51 acute myeloid leukemia (AML)]. Leukemia was considered to be of poor prognosis in cases of refractory disease (n=70), unfavourable karyotype (n=22) or miscellaneous (n=5). All patients had previously received various chemotherapies and 9 had undergone an autologous stem cell transplantation (SCT). The median age at UDS initiation was 25 (range 2.7-55) years. The median time to identify a suitable living donor or cord blood (CB) was 60 days. Eventually, 33 patients received unrelated allo-SCT (including 9 CB), 12 auto-SCT, 39 chemotherapy and 13 palliative treatment. At a median of 54 months, 18 patients were alive, including 15 in remission. The 4-year overall survival rates were 32%, 37%, 15% and 0% for allo-SCT, auto-SCT, chemotherapy or palliative treatment, respectively. Patients who received either allo- or auto-SCT had better survival than those who did not (P<0.0001). For ALL, only allo-SCT significantly improved survival (P<0.007). Finally, patients who received allo-SCT died less often of relapse than patients who did not (P<0.0001). Unrelated allo-SCT gives a substantial long-term survival and cure in patients with high-risk acute leukemia. For patients who achieve remission and for whom UDS fails, auto-SCT may prove to be a good approach. For patients who fail to enter into remission, intensive salvage chemotherapy has a very limited effect.

Impact of Small Bowel Exploration Using Video-Capsule Endoscopy in the Management of Acute Gastrointestinal Graft-versus-Host Disease.

BACKGROUND: The purpose of this study was to evaluate the impact of the global diagnostic approach on the outcome of patients suspected of having acute (a) gastrointestinal (GI) graft-versus-host disease (GVHD). METHODS: Ten consecutive patients with suspected aGI-GVHD were prospectively explored with an exhaustive approach including video-capsule endoscopy (VCE). Images observed with VCE were compared with results obtained with other GI investigations including duodenal biopsies. RESULTS.: Five patients had a normal VCE examination: four were successfully treated symptomatically, but one died as a result of toxoplasmosis. VCE disclosed aGI-GVHD lesions in all five remaining patients, and two of the five were considered normal by upper GI endoscopy. All of these patients experienced improvement in their GI symptoms within 2 weeks of adjustments to their immunosuppressive treatment. CONCLUSIONS: This approach has enhanced the authors' ability to adapt immunosuppressive treatments in patients suffering from suspected aGI-GVHD. Further investigation of the apparently high negative predictive value of VCE will be of great interest, particularly with a view to avoiding unnecessary immunosuppressive treatment.

Abnormal cytogenetics and significant bone marrow plasmacytosis are predictive of early progression and short survival in patients with low tumor mass asymptomatic multiple myeloma.

In order to evaluate the prognostic factors for progression and survival in patients with a low tumor mass asymptomatic multiple myeloma (MM), we studied 59 patients who had a long term follow-up. Cytogenetic abnormalities (using conventional cytogenetics) were observed in 14 out of 45 analyzable patients (31%). An abnormal karyotype and a bone marrow (BM) plasmacytosis > 15% were found to be adverse prognostic factors for progression in univariate and multivariate analysis.

Randomized comparison of double induction and timed-sequential induction to a "3 + 7" induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study.

Between 1990 and 1996, we conducted a randomized trial in adults with newly diagnosed acute myeloid leukemia (AML) in order to compare relapse-free interval (RFI) after double induction (arm B), timed-sequential induction (arm C), or control "3 + 7" induction (arm A). Patients achieving complete remission (CR) after induction +/- salvage received the same consolidation chemotherapy, which included a dosage stratification according to patient's age (younger or older than 50 years). This long-term analysis was performed in 592 patients (arm A/B/C, 197/198/197 patients). Overall CR rate was 76% without differences between the 3 arms, even if a salvage course was less frequently needed in arm B. Treatment-related mortality, either during the induction or the postremission phase, was not significantly higher in arms B and C than in arm A. Among the 449 CR patients, 250 relapsed (arm A/B/C, 90/87/73 patients) without significant differences in RFI in arms B and C versus arm A (P = .39 and .15, by the Gray test). However, when analyzing the 345 patients younger than 50, RFI was significantly improved in younger patients receiving timed-sequential induction (P = .038 by the Gray test), while not in those receiving double induction. Event-free survival and overall survival were similar in the 3 randomization arms.

Dysregulation and overexpression of HMGA2 in myelofibrosis with myeloid metaplasia.

Among cytogenetic studies of patients affected with myelofibrosis with myeloid metaplasia (MMM), a rare chronic myeloproliferative disorder, we found several reports of structural abnormalities of the long arm of chromosome 12. Two MMM patients had a balanced translocation involving 12q: t(4;12)(q32;q15) and t(5;12)(p14;q15), respectively. FISH (fluorescence in situ hybridization) analysis showed that BAC (bacterial artificial chromosome) RP11-366L20 overlaps the breakpoint in both cases. A gene, HMGA2, most of which is included in that BAC, thus was identified as a potential candidate. Using reserves transcriptase-polymerase chain reaction (RT-PCR), we looked for expression of HMGA2 in blood mononuclear cells from these 2 patients and demonstrated a transcript in both. Moreover, we found the gene expressed in the hematopoietic cells of 10 of 10 additional patients bearing no 12q anomalies. HMGA2, not expressed in normal subjects, is implicated in benign solid tumors such as lipomas, leiomyomas, and other rare tumors of mesenchymal origin. We postulate that its dysregulation and overexpression in myeloid progenitors contribute also to the pathogenesis of MMM.

Successful outcome of disseminated Fusarium infection with skin localization treated with voriconazole and amphotericin B-lipid complex in a patient with acute leukemia.

A disseminated Fusarium oxysporum infection with skin localization was diagnosed in a woman with a relapse of B-acute leukemia during induction chemotherapy. The infection was refractory to amphotericin B-lipid complex alone but responded successfully when voriconazole was added.

Three new cases of non-Hodgkin lymphoma with t(9;14)(p13;q32).

The majority of non-Hodgkin lymphomas of B-cell type (B-NHL) exhibit chromosomal abnormalities including many types of reciprocal translocations closely related to specific histopathologic entities. The t(9;14)(p13;q32) has been recognized as a primary genetic event directly involved in the development of lymphoplasmacytic lymphoma. In the 14 published cases, the t(9;14)(p13;32) seems to delineate a variety of low-grade B-cell disorders characterized by a common clinical history and immunopathologic similarities. We report here three new cases presenting a t(9;14)(p13;q32) with other chromosomal abnormalities which have been referred to as B-cell low-grade or high-grade malignant lymphoproliferative disorders. Two of these cases showed diffuse large B cell lymphoma morphology and two patients had a favorable clinical outcome. These data suggest that t(9;14)(p13;q32) is not restricted to low-grade lymphoma.

Karyotypic abnormalities in myelofibrosis following polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative disease characterized by an increase of total red cell volume; in 10% to 15% of cases, bone marrow fibrosis complicates the course of the disease after several years, resulting in a hematologic picture mimicking myelofibrosis with myelocytic metaplasia (MMM). This condition is known as post polycythemic myelofibrosis (PPMF). Among 30 patients with PPMF followed in Northern France, 27 (90%) expressed one or two abnormal clones in myelocytic cell cultures. Of these, 19 (70%) had partial or complete trisomy 1q. This common anomaly either resulted from unbalanced translocations with acrocentric chromosomes, that is, 13, 14, and 15, or other chromosomes, that is, 1, 6, 7, 9, 16, 19, and Y, or from partial or total duplication of long arm of chromosome 1. A single patient had an isochromosome 1q leading to tetrasomy 1q. In all cases, a common trisomic region spanning 1q21 to 1q32 has been identified. Given that most patients had previously received chemotherapy or radio-phosphorus to control the polycythemic phase of their disease, this study illustrates the increased frequency of cytogenetic abnormalities after such treatments: 90% versus 50% in de novo MMM. Moreover, karyotype can be used to distinguish PPMF-where trisomy 1q is the main anomaly-from primary MMM where trisomy 1q is rare and deletions 13q or 20q are far more common. Whether trisomy 1q is or is not a secondary event remains a matter of debate, as well as the role of cytotoxic treatments.

Long-term follow-up of chronic autoimmune thrombocytopenic purpura refractory to splenectomy: a prospective analysis.

Splenectomy remains the most effective treatment of chronic autoimmune idiopathic thrombocytopenia (ITP) (i.e. of > 6 months duration). Treatment of patients refractory to splenectomy (with absence of response or relapse after initial response) is difficult, and their long-term outcome is not well known. Over a 10-year period, 183 patients with chronic ITP were splenectomized including 158 adults and 25 children ( 100 x 10(9)/l, nine of them without treatment and 27 of them with low-dose steroids or azathioprine; six (13%) remained moderately thrombocytopenic (35 x 10(9)/l to 100 x 10(9)/l platelets); the last five patients, without response to any treatment (up to six regimens), remained severely thrombocytopenic (platelets < 20 x 10(9)/l), and three of them died from bleeding. Twenty-seven (57%) of the 47 refractory cases required at least one hospitalization, in the majority of cases for intravenous immunoglobulin (IVIg) infusions. Seven of the refractory cases occurred in children. Six of them subsequently reached platelet counts > 100 x 10(9)/l, but one died from bleeding. Our findings confirm the overall favourable long-term prognosis of chronic ITP refractory to splenectomy.