Jean Pierre Jouet

Prognostic factors in Waldenström's macroglobulinemia: a report of 167 cases.

PURPOSE A single-center retrospective analysis was conducted in 167 patients with Waldenströms macroglobulinemia (WM) to delineate prognostic factors. PATIENTS AND METHODS One hundred sixty-seven patients diagnosed between January 1969 and December 1988, fulfilling diagnostic criteria of WM, were entered onto this study. One hundred twenty-eight patients were treated with chlorambucil (0.1 mg/kg/d): 117 at diagnosis and 11 during the disease course. Seventeen variables were analyzed in all patients and in treated patients for their prognostic value on survival using the Kaplan-Meier method and a Cox multivariate regression analysis. RESULTS Median survival duration for all patients was 60 months. Pretreatment factors associated with shorter survival in the entire population were age > or = 60 years (P = .006), male sex (P = .0001), general symptoms (P = .01), hemoglobin less than 10 g/dL (P = .008), leukocytes less than 4 X 10(9)/L (P = .02), neutrophils less than 1.7 X 10(9)/L (P = .02), and platelets less than 150 X 10(9)/L (P = .0006). Organomegaly, signs of hyperviscosity, renal failure, monoclonal immunoglobulin M (M IgM) level, blood lymphocytosis, and percentage of marrow lymphoid cells were not significantly correlated with survival. In a Cox multivariate regression analysis, the combination of factors that gave the best prognostic value was the association of sex (P = .0002), neutrophils (P = .002), age (P = .008), and hemoglobin (P = .02). CONCLUSION Our findings suggest that some pretreatment parameters, including older age, male sex, general symptoms, and cytopenias, carry a poor prognosis in WM. By contrast, high initial tumor burden (indicated by organomegaly, high IgM level, and high percentage of marrow lymphoid cells) does not seem to be significantly associated with short survival. Our results help define a high-risk population that could perhaps benefit from newer therapeutic approaches.

Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy

Summary. We treated 47 adult patients with de novo myelodysplastic syndrome (MDS) by an anthracycline‐AraC regimen. Median age was 54, and M/F 1·3. At diagnosis, 26 patients had refractory anaemia with an excess of blasts in transformation (RAEB‐T) three had refractory anaemia (RA). 11 had refractory anaemia with excessive blasts (RAEB) and seven had chronic myelomonocytic leukaemia (CMML). Treatment was started within 3 months of diagnosis in 30 patients, and after more than 3 months in the 17 remaining patients. At the onset of treatment, 16 patients had progressed to acute myeloid leukaemia (AML).

Allogeneic Stem-Cell Transplantation As Salvage Therapy for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma Relapsing After an Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow Transplantation Registry

PURPOSE To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkins lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT). PATIENTS AND METHODS The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months. RESULTS Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors. CONCLUSION Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.

Chronic and subacute myelomonocytic leukaemia in the adult: a report of 60 cases with special reference to prognostic factors

We report 60 cases of chronic and subacute myelomonocytic leukaemias (CMML and SMML) in the adult, using the FAB group criteria. The M/F sex ratio was 3·3 and the mean age 67·5 years. Splenomegaly was found in 32% of cases, hyperleucocytosis in 52% of cases and mean blood monocytosis was 4·3 × 109/l. Marrow smears showed an excess of blasts in 57% of patients, a moderate increase in monocytes in most cases and frequent myelodysplastic features. An increase in serum lysozyme and polyclonal hypergammaglobulinaemia were usual and clonal cytogenetic anomalies found in about half of the patients tested. Treatment was usually palliative and the median survival was 28 months, a blastic transformation being responsible for a third of the deaths.

Treatment of Acute Promyelocytic Leukemia: A Report of 70 Cases

Over a period of 14 years, we treated 70 cases of acute promyelocytic leukemia (APL) with 3 different chemotherapy protocols. In protocol 1, patients received high dose daunorubicin (DNR) alone for induction, followed by regular reinduction courses and continuous maintenance therapy with 6 mercaptopurine (6 MP) and methotrexate (MTX) during 3 years. In protocol 2, induction with high dose DNR and Ara C was also followed by regular reinduction courses, but without continuous maintenance therapy. Protocol 3 randomized high dose Amsacrine (AMSA) or Rubidazone in association with Ara C, for induction and consolidation, this was followed by reinduction courses and continuous maintenance therapy with 6 MP and MTX. During the induction all patients received, prophylactic heparinization and platelet transfusions. Fifty six patients (80%) achieved complete remission (CR), 13 patients (18.5%) had early death (ED) or hypoplastic death (HD), and 1 patient had true resistant leukemia. Only two patients died of hemorrhage. Median actuarial disease free survival (DFS) was 16.5 months and a plateau at 29.1% was reached after 29 months. Patients with fever at diagnosis had a significantly lower CR rate while age below 20 years and circulating blasts above 0.5 × 10(9)/1 were associated with shorter DFS. The CR rate did not significantly differ between protocols 1, 2 and 3 (87.5%, 80% and 60% respectively) but 9 of the 30 patients on protocols 2 or 3 had ED or HD, compared to 4 of the 40 treated with protocol 1 (p < 0.05). DFS was significantly shorter in protocol 2, which included no continuous maintenance chemotherapy, than in protocols 1 and 3. Median actuarial survival was significantly shorter in patients treated with protocols 2 or 3, compared to protocol 1. These results suggest that high dose DNR alone, associated with adequate prophylaxis of disseminated intravascular coagulation, gives very high CR rates in APL, with short periods of aplasia and limited toxicity. Combinations of an anthracycline or AMSA at the doses used with regular dose Ara C may be too toxic. Although this was not a randomized trial, our findings also suggest a possible benefit of prolonged continuous maintenance therapy with 6 MP and MTX in APL.

SUCCESSFUL AUTOLOGOUS BONE MARROW TRANSPLANTATION IN INTRAVASCULAR LYMPHOMATOSIS

Intravascular lymphomatosis (IVL) is a large B-cell lymphoma in which neoplastic cells remain within the lumen of small vessels. IVL frequently involves the central nervous system (CNS) and skin. The poor prognosis of IVL may be due to a delay in diagnosis and treatment. Few effective therapies for this rare condition are currently agreed upon (Demirer et al, 1994; Bogomolski-Yahalom et al, 1998). We report, for the first time to our knowledge, a successful second-line treatment with autologous bone marrow transplantation (ABMT) in a patient with refractory IVL. A 52-year-old man presented with fever, sweats, proximal muscle weakness, cough and progressive dyspnoea for 2 months. Performance status was 2. He had neither lymphadenopathy nor hepatomegaly. His spleen was slightly enlarged (2 cm below costal margin). A general physical examination did not show skin and neurological involvement. CT of chest and CT cerebral enhanced scans, lumbar puncture, blood cell counts, bone marrow smear and trephine were normal. Computed tomographic (CT) scan of his abdomen showed only a slightly enlarged and heterogenous spleen (15 × 12 × 9 cm). The lactate dehydrogenase level was 2450 IU/l (range 230– 440). Diagnosis of IVL of B phenotype was obtained by splenectomy (Lagorce-Pagès et al, 1997). A systemic chemotherapy (CHOP regimen: cyclophosphamide, doxorubicin, vincristine, prednisone) with an intrathecal injection of 10 mg methotrexate at each cycle rapidly reduced the B symptoms. After three cycles of CHOP the patient had a seizure followed by a transient right hemiplegia for 72 h, related to an ischaemic process by cranial CT scan and magnetic resonance imaging. At the same time the patient had papulous erythematous skin lesions on his abdomen and thighs. A skin biopsy showed typical intravascular lymphomatosis. Therefore a second-line therapy with VIM2 araC (VP 16– 150 mg/m days 1–3, ifosfamide 1500 mg/m days 1–3, mitoxantrone 10 mg/m days 1–2, araC 2 g/m days 3–4) was started (Bosly et al, 1997). After two cycles the patient was free of symptoms and had no skin lesions. An ABMT was performed 3 months after the first cycle of VIM2 araC. The conditioning regimen combined fractionated total body irradiation (12 grays over 3 d in six fractions) and cyclophosphamide i.v. 50 mg/kg. Engraftment occurred promptly and complete haematological recovery was obtained at day 90. 30 months after ABMT the patient remains alive, free of symptoms and disease, and has returned to work. The poor prognosis in IVL, in the majority of cases, has been related to late diagnosis, especially when neurological involvement was a prominent feature (Demirer et al, 1994). Therapies given for this rare condition have included steroids, radiation therapy, chemotherapy, plasmapheresis (Bogomolski-Yahalom et al, 1998; DiGiuseppe et al, 1994). An aggressive combination therapy (CHOP or equivalent) seemed to be the only treatment able to confer long-term survival (DiGiuseppe et al, 1994). Our case shows that a durable remission can be achieved with a more aggressive approach even in the absence of response and in spite of poor prognostic factors (disseminated lymphoma, high-level LDH). Indeed, treatment by VIM2 araC has been associated with a 68% response rate in high-grade refractory or in relapsed lymphoma (Bosly et al, 1997). This regimen included high-dose araC, a drug with good CNS diffusion. When ABMT is feasible in this disease, it seems reasonable to prefer the marrow as the source rather than peripheral blood CD34 cells for rescue because of the peculiar localization of this lymphoma. Indeed, defective homing and adhesion lymphocyte mechanisms in IVL have been described as responsible for the inability of the malignant cells to extravasate (Jalkanen et al, 1989). This present case suggests that IVL should be treated similarly to other high-grade lymphomas despite peculiar clinical presentation. Therefore aggressive second-line therapy followed by ABMT is a feasible and effective approach in refractory IVL.

The post-transplant cytogenetic response to interferon is a major determinant of survival after autologous stem cell transplantation for chronic myeloid leukaemia in chronic phase

Summary. We have analysed the outcome of 581 autologous stem cell transplants (SCT) for chronic myeloid leukaemia (CML) in first chronic phase reported to the European Group for Blood and Marrow Transplantation between 1983 and 1998. Out off 207 patients evaluable for cytogenetics within 6 months of SCT, 36 patients (17%) were in complete cytogenetic remission (CCR), 34 (16%) in major remission (MCR), 74 (36%) in minor remission (mCR) and 63 (31%) had no cytogenetic response (NR). Interferon (IFN) was given post SCT to 267 patients. Results of the cytogenetic analysis within 1–2 years from SCT were available for 117 patients, the majority of whom (n = 101) received IFN post SCT: 17 (15%) were in CCR, 18 (15%) in MCR, 24 (20%) in mCR and 58 (50%) NR. The median survival in this series was 96 months (71–125) from SCT. There was no difference in survival according to cytogenetic status pre‐ and immediately post SCT. However, patients in CCR or MCR at 1–2 years post SCT had a 10‐year survival of 66% compared with 36% for patients in mCR or NR (P = 0·003). The 5‐year survival for patients receiving IFN post SCT was 72% compared with 61% for patients not treated with IFN (P = 0·01). Out of 155 patients refractory to IFN pre SCT, 70% achieved a cytogenetic response post SCT, which was complete or major in 31%. IFN refractory patients who sustained a CCR or MCR for 1–2 years after SCT had an excellent outcome.

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the severe aplastic anaemia working party of the European society for blood and marrow transplantation

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17 days, respectively. Grade II‐IV acute graft‐versus‐host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow‐up of 3·5 years, the 5‐year overall survival (OS) was 60·7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score ≥80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.

Growth factor-associated graft-versus-host disease and mortality 10 years after allogeneic bone marrow transplantation

This study analysed the effects of growth factor on outcome after haematopoietic stem‐cell transplantation (HSCT) with >9 years follow‐up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)‐identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft‐versus‐host disease (GVHD)‐free survival (no acute GVHD grade II–IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD‐free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non‐relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15–1·9; P = 0·002; HR = 1·59; 95% CI: 1·07–2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78–1·18; P = 0·71). Leukaemia‐free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60–0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI.

Management of psychiatric complications in unrelated donor before unrelated peripheral hematopoietic stem cell collections

Allogeneic hematopoietic stem cell transplantation can efficiently treat patients with severe hematological diseases. A human leukocyte antigen-compatible donor is required for performing transplantation. The occurrence of unexpected acute severe diseases in a donor can compromise the feasibility of allogeneic hematopoietic stem cell transplantation. However, when a severe health problem occurs in a donor while the recipient has already received a conditioning regimen, hematologists have to find the best solutions for the recipient, while the team in charge of the donor has to find the best medical solutions for the donor. We describe here the occurrence of psychiatric acute complications in an unrelated donor while the myeloablative conditioning regimen had already been given to the recipient. We report the successive decisions that were made in an emergency based upon the expertise of physicians specialized in hematology, apheresis, cell therapy, and psychiatry to preserve the donor’s health and recipient’s life.