Double reduced-intensity allogeneic hematopoietic stem cell transplantation: a retrospective study from the SFGM-TC.

The purpose of this paper is to describe the outcome of patients who underwent double allogeneic hematopoietic stem cell transplantation (AHSCT) with reduced-intensity conditioning regimens (RIC). Forty-five patients who received double RIC-AHSCT between 1997 and 2006 were retrospectively studied. The predominant diagnosis was acute myeloid leukemia (AML) (n = 17). Other diagnoses were aplasic anemia (AA) (n = 5), myelodysplasic disorder (n = 5), acute lymphoblastic leukemia (ALL) (n = 4), chronic myelomonocytic leukemia (CML) (n = 3), myeloma (n = 3), non-Hodgkin lymphoma (NHL) (n = 3), chronic lymphocytic leukemia (CLL) (n = 2), Hodgkin's disease (HD) (n = 2), and chronic myelomonocytic leukemia (n = 1). Main indications for RIC-AHSCT 2 were relapse (n = 25, 56%) and early (n = 8, 18%) or late (n = 12, 26%) graft failure. Median delays to reach a neutrophil count of 0.5 × 10(9)/L and platelet counts of 50 × 10(9)/L were significantly smaller after the second AHSCT. Among 25 patients who relapsed after RIC-AHSCT 1, 14 patients (56%) presented a response improvement after RIC-AHSCT 2. In this group, 9 patients sustained a complete response and 5 patients a partial response. Moreover, among the 20 patients who had early or late graft failure following RIC-AHSCT 1, 9 (45%) finally reached an engraftment. Disease-free survival (DFS) was significantly improved after RIC-AHSCT 2. Thirteen patients (28%) died of transplant-related mortality (TRM) at a median delay of 69 days (range: 0-451) after RIC-AHSCT 2. Double RIC-AHSCT is a feasible procedure that allows a response or engraftment not observed after RIC-AHSCT 1. The main indication is relapse. However, TRM remains high.

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Prophylactic use of ganciclovir for allogeneic bone marrow transplant recipients.

Ganciclovir which has proved effective in the treatment of cytomegalovirus (CMV) infection was given prophylactically to 40 bone marrow transplant (BMT) patients pre and post-transplant in seropositive patients and post-transplant in seronegative patients with a seropositive donor. All patients were transfused with screened blood products and 33 received CMV hyperimmune globulin. They were compared with an historical control group consisting of 39 patients who had received significantly more unscreened blood products (p = 0.01) and less HLA-mismatched marrow transplants (p = 0.05). Toxicity of ganciclovir was hematological-neutropenia was responsible for cessation of the drug in seven patients and transfusion requirements were significantly higher in the ganciclovir group. Non-hematological toxicity did not occur in any patient. Only one patient (2.5%) experienced symptomatic CMV infection and no patient developed CMV pneumonitis. In contrast, in the control group, 23 (59%) patients had clinical symptoms of CMV infection (p < 0.0001) and 4 (10%) experienced CMV pneumonitis (p < 0.01). Ganciclovir significantly reduced the incidence of positive CMV antigenemia (7.5% in the treated group vs 72% in the control group; p < 0.01). However, ganciclovir delivery did not result in an improved overall survival due to a higher rate of regimen-related deaths and chronic GVHD mostly in patients transplanted from an HLA-mismatched donor. The prophylactic administration of ganciclovir abrogates CMV pneumonitis and considerably reduces the incidence of CMV infection in BM recipients at high risk of developing this disease after transplantation.

Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome.

Donor lymphocyte infusion has become established as a salvage therapy for patients with hematological disorders relapsing after allogeneic bone marrow transplantation (BMT). The role of donor lymphocyte infusion for patients with myelodysplastic syndrome (MDS) remains to be established. Between July 1993 and October 2001, 14 patients with MDS relapsing after allogeneic BMT received DLI as salvage therapy. At the time of BMT, one patient had RA, nine had RAEB, of whom three were in CR after induction-type chemotherapy, two had RAEB-T, one had CMML and one had AML. Donors were HLA-matched siblings (n=12), HLA-matched other relative (n=1) and unrelated (n=1). At the time of relapse, the median marrow blast count was 9%. The median CD3+ cell dose administered was 6.3 x 10(7)/kg. With a median follow-up of 49 months, six patients were alive, of whom two were in CR after DLI alone and remained disease-free, two were in CR after a second BMT and two had active disease. Eight patients died of disease progression. Although DLI alone seems to be effective in a small number of patients with MDS, other treatment strategies, including prior debulking chemotherapy, deserve investigation.

Donor search or autografting in patients with acute leukaemia who lack an HLA-identical sibling? A matched-pair analysis. Acute Leukaemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and the International Marrow Unrelated Search and Transplant (IMUST) Study.

One hundred and ninety-one patients with acute leukaemia who received bone marrow from HLA-A, -B and -DR identical unrelated donors and were reported to EBMT and/or IMUST, were matched with 382 patients receiving autologous bone marrow for diagnosis, age, stage of disease and year of transplantation. Transplant-related mortality (TRM) was significantly higher in recipients of unrelated marrow compared to autograft recipients, 44 +/- 4% (+/- 95% confidence interval) and 15 +/- 3% at 2 years in the two groups, respectively (P < 10(-4)). In contrast, relapse probability was lower in recipients of unrelated marrow, being 32 +/- 5% at 2 years compared to 55 +/- 3% in recipients of autografts (P < 10(-4)). Two-year leukaemia-free survival (LFS) in patients with acute lymphoblastic leukaemia was 39 +/- 5% and 32 +/- 3% in the two groups, respectively. Among patients with acute myeloid leukaemia (AML), the corresponding figures were 36 +/- 6% and 46 +/- 5% in the two groups, respectively (P = NS). In AML in first remission (CR-1), the 2-year survival was 42 +/- 10% in recipients of unrelated bone marrow, compared to 69 +/- 8% in autograft recipients (P = 0.008). When all patients with acute leukaemia were included, the 2-year LFS was 38% in recipients of unrelated marrow, compared to 37% in autograft recipients (NS). In conclusion, this retrospective analysis supports the design of a prospective randomized study in patients with high-risk/advanced acute leukaemia who lack a suitable related bone marrow donor, to ascertain which of the two strategies, if any, should be favoured.

Allogeneic Bone Marrow Transplantation in Chronic Lymphocytic Leukemia: 17 Cases. Report of the EBMT.

Allogeneic bone marrow transplantation (BMT) was performed in 17 patients with chronic lymphocytic leukemia (CLL): 15 resistant and 2 untreated forms; 12 males and 5 females with a mean age of 40 years (32-49). The conditioning regimen and graft versus host disease (GVHD) prophylaxis were varied. Successful engraftment was obtained in 15 evaluable cases. Lymphocytosis and clinical symptoms subsided in all but one case. All 15 evaluable patients developed acute GVHD. Among the 17 patients grafted, one early death was observed at the 15th day post-BMT, and one refractory form died 2 months after BMT. Of the remaining 15 patients in complete remission (CR0, 4 died from GVHD, hemorrhage, and graft failure, and 2 relapsed at 7 and 54 months after BMT and died. 9 patients are alive in CR with a mean follow-up of 25.6 months (4-48). Chimerism was complete in 8 patients and partial in the 2 T-depleted cases. In one case, an immunoglobulin gene rearrangement study was performed showing no residual disease. These results suggest that allogeneic BMT might be proposed as an alternative and possibly curative therapy for refractory CLL in young patients when performed earlier in the disease course.

[Immediate hematological toxicity during combination chemotherapy-radiotherapy of Hodgkin's disease]. / Toxicité hématologique immédiate au cours de l'association chimiothérapie-radiothérapie dans la maladie de Hodgkin.

The hematologic immediate toxicity during radiotherapy for Hodgkin's disease was studied from a series of 72 patients with stage IIB or III who received 3 courses or more of chemotherapy before radiotherapy. The toxicity in the group of 36 of them who received total nodal irradiation (TNI) was the most important. Sixteen of the 28 TNI had irradiation interrupted, 12 of them began with inverted Y type. The blood cells count at the beginning of the treatment was crucial; only 16% of the patients had interruption of irradiation when the blood cells count was normal; on the other side, 63% had interruption when the blood cells count was abnormal (P less than 0.05). Toxicity was due to the daily destruction of the dividing bone marrow stem cells located in the irradiated area, from the first day of treatment; there was a progressive decrease in the pool of these stem cells within a late resaturation. The absence of resaturation of this pool after initial chemotherapy and after the first part of irradiation explained the immediate and durable toxicity; in the same way, inverted Y irradiation destroyed a great part of active bone marrow (40%) and the pool of remaining stem cells with high mitotic index would be located in areas irradiated subsequently. So, waiting for the absolute normalisation of blood cells count before beginning irradiation and start irradiation by mantle field (rather than inverted Y) seem to be the 2 measures able to reduce the number of interruptions of irradiation due to hematotoxicity.

[Methotrexate pneumonitis arising during the treatment of non-Hodgkin's lymphomas with the m-BACOD protocol]. / Pneumopathies du méthotrexate survenant dans le cadre du traitement des lymphomes non hodgkiniens par le protocole m-BACOD.

We retrospectively studied 32 patients treated with the m-BACOD regimen in a single institution between January 1988 and December 1991. After four to seven courses, four patients presented severe acute pneumonitis (PaO2 < 55 mmHg in room air), with diffuse bilateral interstitial syndrome. Broncho-alveolar lavage displayed increased lymphocyte count (> 45%) with inversion of CD4/CD8 in two cases and no evidence of parasitic, bacterial or viral infection. All patients received methyl-prednisolone (0.5 to 1 mg/kg/d x 1 week) with both complete clinical and radiological recovery within a week. The m-BACOD regimen was continued without bleomycine for four patients and without bleomycine plus methotrexate for two patients, until the completion of eight courses, without recurrence of pneumonitis. Drug-exclusion decisions were made empirically because the exact nature of the pneumonitis was not recognized at the time of diagnostic. Because of the regular administration in the m-BACOD regimen, methotrexate leads to an increased risk of pneumonitis. We concluded that the use of the m-BACOD regimen should henceforth be discontinued.

[Atrial systole. Study of its role in the normal subject and in left ventricular insufficiency]. / La systole auriculaire Etude de son rôle chez le sujet normal et dans l'insuffisance ventriculaire gauche

In order to study the importance of atrial systole, the authors used different stimulus modalities at the same rate; they stimulated the right ventricle, the right atrium, and the two. The haemodynamic parameters were monitored by microcatheterisation of both right and left sides. A comparative study using controls and patients with left ventricular failure showed the improvement in the haemodynamic picture which was obtained in the latter group when the atrio-ventricular sequence was correct.

[Hemocynamic role of atrial contraction in the acute phase of myocardial infarct]. / Rôle hémodynamique de la contraction auricularie dans l'infarctus du myocarde ó la phase aiguë

The authors have studied the haemodynamic role of atrial systole in patients in the acute stage of a myocardial infarction, usually with left ventricular failure. Their main comparison is between the results obtained with stimulation of the right ventricle at a fixed rate and those obtained with bifocal stimulation, thus restoring the atrio-ventricular sequence. The authors discuss their results, and especially their findings of improvement in cardiac output and systemic arterial blood pressure. They raise the question of synchronous stimulation in cases of infarction with heartblock complicated by left ventricular failure, and also of re-establishing sinus rhythm in cases of arrhythmia of supraventricular origin.

[Acute leukemia secondary to the treatment of multiple sclerosis with chlorambucil]. / Leucémie aiguë secondaire au traitement de la sclérose en plaque par le chlorambucil.

A new case is reported here of acute myeloid leukemia after chlorambucil therapy for multiple sclerosis. This is the sixth case seen at our institution during the period 1978 to 1984. The leukemogenic potential of the immunosuppressive cytotoxic drugs in patients with multiple sclerosis is emphasized.

[Cost effectiveness of GM-CSF in the treatment of acute myeloblastic leukemia in aged patients: protocol of GOELAM Sa3]. / Intérêt thérapeutique et économique du GM-CSF dans le traitement des leucémies aiguës myéloblastiques du sujet âgé: protocole GOELAM Sa3.

A cost-effectiveness analysis was carried out from a randomized placebo-controlled protocol of GM-CSF during and after remission induction treatment for elderly patients with acute myeloid leukemia (AML). A retrospective economic analysis was carried out from the hospital perspective. A total of 240 patients with de novo AML and aged 55 to 75 years were enrolled. Overall survival and disease-free survival were analysed for efficacy within five years and expressed in gained life-years. Analysis was also conducted according to the protocol stratification: 55-64-year-old and 65-75-year-old patients. Global costs were estimated on the basis of patient medical records from inclusion to death or relapse. In all, 83 patients were evaluated from three centres, Besançon, Nancy and Nantes. Costs are expressed in French francs. Overall, total cost per patient amounted to FF 641,778 for placebo patients and to FF 587,048 for GM-CSF patients. For disease free-survival, costs were FF 357,167 for placebo patients and FF 320,736 for GM-CSF patients. For overall survival and disease free-survival the cost savings by GM-CSF were, respectively, FF 54,730 and FF 36,431. In the younger patient group savings were synonymous with GM-CSF. In all cases GM-CSF strategy induced benefit expressed as savings as well as efficacy.

[1 alpha 25-dihydroxyvitamin D3 (calcitriol) and malignant hemopathies. Decreased serum levels in acute leukemia: preliminary results]. / 1 alpha 25-dihydroxyvitamine D3 (calcitriol) et hémopathies malignes. Taux sériques diminués dans les leucémies aiguës: résultats préliminaires.

We used the Amersham radioimmunological method to measure plasma 1 alpha 25-dihydroxyvitamin D3 (calcitriol) levels in patients presenting with one of the following diseases: (i) non-acute myelodysplastic syndrome (39 cases); (ii) acute myeloid leukaemia in blastic phase (43 cases) or in complete remission (15 cases) and (iii) acute lymphoid leukaemia in blastic phase (11 cases). All patients had normal metabolic functions. Compared with our standard laboratory values (15-35 pg/ml), the results of these assays were related to the type of pathology or, in patients with acute myeloid leukaemia, to the stage of the disease (p less than 0.001). Moreover, the mean plasma calcitriol values differed according to the type of pathology (p less than 0.003). Patients with acute myeloid leukaemia in blastic phase had a low level of calcitriol as compared with controls (p less than 0.05) and with patients with acute myeloid leukaemia in complete remission (p less than 0.001) whose calcitriol levels were never low. In contrast, there was no significant difference between controls and patients with myelodysplastic syndrome or acute lymphoid leukaemia in blastic phase. This study demonstrates the usefulness of plasma calcitriol assays in malignant blood diseases where low values in certain types of leukaemia would incite to include calcitriol in therapeutic regimens.

[Realization of an assisted system for medical decision and follow-up in hematologic diseases treated with sequential chemotherapy]. / Réalisation d'un système d'aide à la décision médicale et au suivi pour les hémopathies traitées par chimiothérapie séquentielle.

The follow-up of patients treated with sequential chemotherapy in internal medicine departments with special interest in haematology imposes a heavy burden on the entire treating staff. The chances of errors, notably in medical prescriptions and care, are not negligible, and these errors result in iatrogenic complications, readmissions and prolonged stays in hospitals. Designing a medical decision and therapeutic follow-up aid system should be time-saving for the staff and ensure good quality and safe prescriptions as well as reliable therapeutic evaluations and better hospital management. The system described here is developed on 4D Macintosh computer which handles a relational data-base. It includes the data-base, i.e. a knowledge-based system devised by the expert clinician containing "declarative" data and deduced rules which represent the expert's reasoning and determine the action to be taken, and the interface between them. The system easily accepts many parameters, thereby enabling medical knowledge and therapeutic attitudes to be updated.

[Acute drug-induced agranulocytosis. Clinical study apropos of 30 patients and evolution of etiologies over 2 decades]. / Agranulocytoses aiguës médicamenteuses. Etude clinique à propos de 30 patients et évolution des étiologies sur 2 décennies.

Between 1982 and 1993, 30 patients were treated for drug-induced agranulocytosis. They did not receive cytotoxic chemotherapy nor radiotherapy during the past 6 months. There is a higher incidence in women (21 females, nine males). Mean age is 59.3 years old. The drug could be found in 25 cases including noramidopyrine five cases, antithyroid drugs four cases, non steroidal anti-inflammatories drugs four cases. Five patients died of infection during agrulocytosis. Sepsis was documented in three cases. We used hematopoietic growth factors in two cases. Neutrophils rose up to 0.5.10(9)/l between 2 to 14 days after the diagnosis and 1.10(9)/l between 3 to 16 days. Time when absolute neutrophil count was less than 0.5.10(9)/l was shorter (p = 0.008) when bone marrow was rich with maturation arrest but with few or no mature forms rather than reduction of granulocytic precursors. By comparison with a similar study made in the same institution between 1971 and 1981, there were fewer cases each year. Drugs involved were not similar: phenicols were not found, reference to noramidopyrine is less frequent. Now antithyroid drugs is becoming one of the most important etiologies.

[Value of high-dose cytosine-arabinoside in the treatment of resistant acute leukemia]. / Intérêt des hautes doses de cytosine-arabinoside dans le traitement des leucémies aiguës résistantes.

Sixty-one patients with refractory or relapsed or secondary acute leukemia were treated with high-dose cytosine arabinoside (2-3 g/sq m in intravenous infusion every 12 hr to a 12-36 g/sq m total dose). m-Amsa or another antileukemic drug was given with cytosine arabinoside to 20 patients. Complete remission was achieved in 12 of 27 patients with acute myeloid leukemia, 5 of 8 patients with chemotherapy-induced leukemia, 3 of 7 patients with hematologic disorders in blastic crisis and 5 of 17 acute lymphoblastic leukemia patients. A similar response rate (6/16) was obtained when m-Amsa was given with cytosine-arabinoside. The median duration of remission was short (4 months in acute myeloid leukemia). Bone marrow transplantation was performed in 10 patients during the remission time. This regimen has acceptable toxicity; severe neurologic or hepatic disorders occurred in 18% of patients. These data suggest that high-dose cytosine arabinoside is an effective alternative in the treatment of resistant acute leukemia.

[Granulocyte sarcoma of the pancreas without extra-pancreatic location]. / Sarcome granulocytaire du pancréas sans autre localisation extra-pancréatique.

INTRODUCTION: Granulocyte sarcoma (GS), also known as chloroma, is a localized malignant tumor composed of myeloid cells, the diagnosis of which is difficult. The pancreatic location and recurrence, aside from any context of malignant hemopathy, are exceptional. OBSERVATION: A 31-year-old woman developed an isolated and recurrent granulocyte sarcoma of the pancreas, without any context of a malignant hemopathy. The diagnosis retained on extemporaneous examination was an adenocarcinoma of the pancreas, because of the non-specific necrotic nature of the tumor. The immuno-histochemical exploration corrected the diagnosis. Despite local surgery, an isolated tumor recurred 6 months later. This relapse was treated with radiotherapy followed by heavy chemotherapy, identical to that applied in acute myeloblastic leukemia (AML). Ten months later, remission was stable and complete. COMMENTS: Isolated granulocyte sarcomas located in the pancreas are exceptional and have often led to initial erroneous diagnosis. Immuno-histochemical methods are essential in order to obtain correct diagnosis. Despite the localized nature of the tumor, intensive AML-type chemotherapy is necessary.

A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse.

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.