Philadelphia chromosome in human multiple myeloma.

Four patients with multiple myeloma in whom a Ph1 chromosome was found were described; 1 patient had a (9;22) translocation, 2 had no evidence of a translocation, and 1 had a complex translocation (3;8;22). Ph1 chromosomes with standard (9;22) or with unusual translocations were recently found in various myeloproliferative disorders (other than chronic myelogenous leukemia) and in acute lymphoblastic leukemia. These findings point to the genesis of a Ph1 chromosome in diseases other than chronic myelogenous leukemia and other myeloproliferative disorders.

Cyclosporin A in the treatment of refractory B chronic lymphocytic leukemia (B-CLL).

Partial tumoral responses have been described after cyclosporin A treatment in refractory B-chronic lymphocytic leukemia patients. We report the effect of this therapy in five patients prospectively treated with oral conventional dose of cyclosporin A. Antitumoral efficiency was marginal (one sustained partial response among five patients) which, added to a potential worsening of natural and therapy-related immunodepression, limits its use in this instance.

Extra translocation +der(1q9p) is a prognostic indicator in myeloproliferative disorders.

An identical extra derivative chromosome resulting from a translocation between the long arm of chromosome 1 and the short arm of chromosome 9, +der(1q9p), has been observed in three patients with a myeloproliferative disorder. Two patients had polycythemia vera in transformation (erythroleukemia in one patient and refractory anemia in the second), whereas the third patient had myelofibrosis which later evolved into acute myelomonocytic leukemia. The two patients who developed overt leukemia did not receive any previous cytotoxic treatment. Non-isotopic in situ hybridization was performed in two patients, allowing for the localization of the breakpoints in 1q12 and 9q12. A similar rearrangement has been previously described in patients with polycythemia vera, either at diagnosis or in advanced stages of the disease. These data suggest that this chromosome abnormality may be consistently associated with myeloproliferative disorders showing a high propensity to transformation, which is not treatment related, and the finding of the +der(1q9p) may represent a poor prognostic sign when observed in the chronic phase.

2-Chlorodeoxyadenosine (CdA) for patients with previously untreated chronic lymphocytic leukemia (CLL).

The encouraging therapeutic results attained with the purine analogue CdA in patients with previously treated CLL prompted us to assess its potential in untreated CLL patients. Nineteen patients, 13 males and six females, median age 65 years (range 27-75), with previously untreated CLL were given monthly courses of CdA, 0.12 mg/kg/day as 2-h i.v. infusions for 5 days, until maximum response or excessive toxicity. Five patients with Binet's stage A, 10 with stage B and four with stage C CLL entered the study. After a median of five courses of CdA (range 1-9) nine complete responses (CR = 47%, CI: 24-69%), five partial responses (PR = 26%, CI: 7-46%) and five failures (= 26%, CI: 7-46%) were recorded. In five complete responders and in one partial responder cytofluorometric analysis of blood and/or bone marrow failed to demonstrate a residual clonal B cell population. A search for residual disease by PCR technology and by immunostaining of bone marrow biopsies however disclosed residual leukemic cells in these six cases. Adverse reactions included fever of unknown origin (n = 3), pneumonia (n = 2), herpes simplex infection, herpes zoster, an anal abscess, a cutaneous rash, autoimmune hemolysis and mental disturbance (one patient each). In this small cohort, neither age, stage, blood counts, cytogenetics or pattern of bone marrow infiltration at inclusion were predictive for response. From these preliminary data, we conclude that CdA has remarkable short-term efficacy in patients with previously untreated CLL. However, toxicity is not negligible and long-term benefit from therapy with CdA still has to be established.

Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria.

609 patients with B cell chronic lymphoproliferative disorder were studied with the primary aim of analyzing the cytogenetic profile of B cell chronic lymphocytic leukemias and, if possible, define correlations with FAB classification of these diseases. Morphological and immunological studies were performed according to criteria proposed by the FAB group. A panel of monoclonal antibodies, including at least sIg, CD19, CD5, and FMC7 was used. Interpretations of morphology and cytogenetics were made independently. When applying strict FAB criteria 65% of the cases could be classified. Most of them (44%) were chronic lymphocytic leukemia (CLL). The cases not satisfying strict FAB criteria could be divided into two groups: one closely related to CLL, and here defined as atypical CLL (aCLL) (21%) and another group consisting of patients with leukemic manifestations of B cell non-Hodgkin's lymphoma (LL) (14%). Analyzable metaphases were obtained in 89% of patients. Clonal abnormalities were present in 35% of patients. The most frequent chromosomal changes were abnormalities of chromosome 11q (60 cases), trisomy 12 (46 cases) and structural rearrangements of chromosome 14q (44 cases). Statistical associations with FAB subtypes were found: aCLL and trisomy 12 (P < 0.00001); mantle zone lymphoma (MZL) and t(11;14) (P < 0.00001) and del(6)(q) (P < 0.0001); CLL/mixed cell type and del(6)(q) (P < 0.002); follicular lymphoma and t(14;18) (P < 0.00001); splenic lymphoma with villous lymphocytes and del(7)(q) (P < 0.0004); leukemic lymphoma (LL) with rearrangements in chromosome 9q (P < 0.0001) and trisomy of 3 (P < 0.001). Chronic lymphocytic leukemia was not statistically associated with any specific chromosomal abnormality. However, this subtype showed a high incidence of del(11)(q) and rearrangements of 13q. This study confirms the value of cytogenetic investigation in the diagnosis of these disorders and may provide some new elements for future refinement of the FAB classification in mature B cell lymphocytic disorders.

P190 BCR/ABL transcript in a case of Philadelphia-positive multiple myeloma.

Philadelphia positive multiple myeloma is a very rare event and, so far, no molecular data about the involvement of the BCR and C-ABL genes are available. We report here the case of a 64-year-old woman presenting with a typical multiple myeloma and a complex Philadelphia (Ph) chromosome that we investigated at a molecular level using conventional DNA techniques and the polymerase chain reaction (PCR). No rearrangement was observed within the major breakpoint cluster region (M-BCR) although she was found to have a P190 BCR/ABL hybrid transcript using PCR. As far as we know, this is the first description of a P190-type mRNA in a patient with a chronic lymphoid disorder. Since P190 is almost always associated in man with acute forms of hematological malignancies, this suggests that other factors may play a role in determining the phenotype of the disease.

5q- anomaly in lymphoid disorders.

Observations made in two patients and a review of the literature confirm the occurrence of a 5q- chromosome anomaly in lymphoproliferative disorders of both T and B cell type. Additional chromosome changes were invariably present and are of the "lymphoid" type. The chromosome morphology of the 5q- is indistinguishable from that found in myeloid disorders.

Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RAR alpha patient.

All-trans retinoic acid (ATRA) is a potent inducer of differentiation and cell death in malignant cells. Its effect is known to be mediated through binding to specific nuclear (RARs and RXRs) or cytoplasmic (CRABP) proteins. ATRA is strikingly effective in acute promyelocytic leukemia (the AML3 subtype) inducing a high incidence of complete remissions. Paradoxically, most AML3 cells harbor an abnormal retinoic acid receptor (PML/RAR alpha) resulting from the t(15;17) translocation. Though few AML3 patients do not respond to ATRA therapy, individualization of these cases is of practical importance. Recently the RAR alpha gene has been demonstrated to be involved in a novel fusion transcript (PLZF/RAR alpha) through a t(11;17) translocation. We describe here the second case of such a patient with a t(11;17)-PLZF/RAR alpha leukemic clone. Southern analysis revealed that the breakpoint in the RAR alpha gene was within the second intron (as for PML/RAR alpha) and the intron separating the second and third zinc finger of the PLZF gene. In vitro, the leukemic cells did not show increased NBT reduction or loss of self-renewal after incubation with ATRA. After therapy with ATRA, only partial remission was obtained. These results suggest that the t(11;17) (PLZF/RAR alpha) case of this study was less responsive to ATRA therapy than t(15;17) (PML/RAR alpha) cases and raises the question of the definition of this novel AML subtype.

Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma.

Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m2/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m2, and was escalated by 100 mg/m2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m2, was 300 mg/m2. Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% CI, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenström macroglobulinemia.

Age-adapted induction treatment of acute lymphoblastic leukemia in the elderly and assessment of maintenance with interferon combined with chemotherapy. A multicentric prospective study in forty patients. French Group for Treatment of Adult Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its poor prognosis. Forty patients with ALL, aged 55 years or older, and with good performance status (ECOG <3) were prospectively treated according to an age-adapted regimen: induction therapy was derived from the LALA87 protocol while the feasibility of treatment with interferon combined with chemotherapy was assessed during maintenance. Compared with younger adults treated according to the LALA87 protocol, elderly patients did not present with more adverse prognostic features, except for a lower incidence of T cell ALL (9 vs 31%, P=0.005). There were even less patients with a high leukocyte count (15 vs 38%, P=0.003), a characteristic associated with adverse prognosis while the incidence of Philadelphia-positive (Ph-positive) ALL was not significantly increased compared to younger adults (31 vs 20%, P=0.2). After completion of induction therapy, with or without salvage treatment, 85% (CI: 70-94%) obtained a complete response (CR) while treatment-related mortality during induction was 7.5% (CI: 2-20%). Median overall survival and disease-free survival were 14.3 months and 14 months, respectively, which, although inferior to results achieved in younger adults, compares favorably with available data in the elderly. Treatment with IFN proved feasible in most patients but had to be discontinued in eight patients because of toxicity. Age-adapted treatment improves the prognosis of ALL in the elderly even if, in most cases, a cure cannot be achieved.

[The solitude of Bartók: a hidden life]. / Solitude Bartók: une leucémie cachée.

The destiny of Bartók is closely related to that of his native land, Hungary. His life endured History's hazards and destiny's whims. It was a trip strewn with obstacles and marked by afflicting health problems; it went through boisterous conflicts and captivating passions, met the injuries of lack of understanding and the bruises of the unvoiced comment. This particular course opened the musician to the ethnomusicology and led him to the creation of original musical works. The exile towards the new world generated difficulties and creativity. An insidious disease mortgaged the future of this uprooted and, in several stages, led him to death. The periods of respite animated his creative genius and generated immortal works.

In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin's lymphoma using positron emission tomography.

Carbon-11 thymidine (TdR) uptake using positron emission tomography (PET) has been measured in ten patients with non-Hodgkin's lymphoma (NHL). The rate of TdR uptake (mean +/- s.d.) was of 0.009 +/- 0.006 mumol.100 cc-1.min-1 in low-grade NHL. This rate was 0.063 +/- 0.049 mumol.100 cc-1.min-1 in intermediate-grade NHL and 0.159 mumol.100 cc-1.min-1 in a patient with high-grade NHL. Lymphoma radioactivity reached a plateau at 0.42 +/- 0.22%. 100 cc-1 of the injected dose from 10 min after injection. The highest 11C uptakes were observed in the kidneys and in the liver (3.30 +/- 1.30 and 2.10 +/- 0.05%. 100 cc-1 of the injected dose, respectively). The lymphoma-to-muscle ratio was of 11.8 +/- 1.7, whereas the lymphoma-to-intestine ratio was of 1.5 +/- 0.7. Accordingly, the measurement of [11C]TdR uptake in the abdomen may need other imaging methods for adequate interpretation. The results suggest that [11C]TdR uptake using PET might be a method for noninvasively measuring cell proliferation in vivo.

Translocation t(8;10)(q12;p14) in lymphoproliferative disorders.

Cytogenetic studies were performed in two patients with a B-cell lymphoproliferative disease in progressive phase characterized by leukocytosis and important splenomegaly. In both patients an identical chromosome marker derived from a t(8;10)(q12;p14) translocation was found. This chromosome anomaly was associated with other abnormalities characteristic for lymphoid malignancies, i.e. a structural rearrangement of the long arm of chromosome 11 and a 14q+ in both patients. This new t(8;10) translocation may be a marker of accelerated phase in lymphoid disorders.

Rearrangements of the short arm of chromosome No. 6 in T-cell lymphomas.

Cytogenetic studies on four patients with T-cell lymphomas are reported. In all four the short arm of chromosome No. 6 (6p) was abnormal. In three cases it was involved in a translocation, and in one there was a deletion of the terminal part: del(6)(p23-24). One of the translocations could be identified as a t(2:6)(q24;p24). Identification was not possible in the others. These 6p anomalies were associated with complex structural and numerical abnormalities of other chromosomes in three out of four cases. In three patients chemo- and/or radiotherapy administration preceded cytogenetic investigations.

Mature plasma cells as indicator of better prognosis in multiple myeloma. New methodology for the assessment of plasma cell morphology.

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Additional myeloablation with 52Fe before bone marrow transplantation.

For many hematological malignancies, high-dose chemoradiotherapy followed by bone marrow transplantation offers the best and sometimes the only chance for cure. However, the main causes of failure of this therapy are relapse and toxicity. In order to selectively deliver higher doses of radiotherapy to the bone marrow and to spare normal organs, we explored 52Fe therapy before a conventional BMT conditioning regimen. Twenty-four patients at high risk for relapse after BMT were included in a phase II study. The median follow-up was 42 months. The median 52Fe dose was 59 mCi. This resulted in a median radiation-absorbed dose (RAD) to the BM of 626 rad. The median RAD to the liver was 338 rad. No untoward effects were noted after the injections of 52Fe. The patients recovered hematopoiesis without toxicity in excess of that expected with conventional conditioning alone. The 3-year DFS probability was 49% (95% CI: 20-78%). Eight patients have relapsed, three of them in extramedullary sites. 52Fe should provide a way to boost the radiation dose to marrow-based diseases before bone marrow transplantation without excessive toxicity.

Interferon alpha induced and maintained complete remission in chronic granulocytic leukemia in relapse after bone marrow transplantation.

We describe a patient with chronic granulocytic leukaemia (CGL) who relapsed after allogeneic bone marrow transplantation (BMT). Interferon alpha 2b (IFN alpha 2b) induced and maintained a complete remission. IFN alpha 2b led to full restoration of donor bone marrow. This case provides evidence to support a trial of IFN alpha in patients with relapsing CGL after BMT.

Prophylaxis of graft-versus-host disease in identical sibling donor bone marrow transplant by anti-IL-2 receptor monoclonal antibody LO-Tact-1.

The efficacy of the rat monoclonal IgG2b antibody LO-Tact-1 specific for the human interleukin-2 (IL-2) receptor was evaluated for prophylaxis of graft-versus-host disease (GVHD) in patients who received transplants of marrow from HLA-matched sibling donors. Fifteen patients received cyclosporine (CsA) + antibody LO-Tact-1, 0.2 mg/kg/day from day +7 to day +28. Twelve additional patients were administered methotrexate (MTX) + CsA+antibody LO-Tact-1, 0.4 mg/kg/day from day -1 to day +28. The antibody was well tolerated. Engraftment was not affected. GVHD grade > or = II occurred in six of 15 and eight of 12 patients receiving CsA+LO-Tact-1 and MTX+CsA+LO-Tact-1, respectively (P = 0.52). GVHD grade > or = II developed in patients at a median of 32 and 34 days with CsA+LO-Tact-1 and MTX+CsA+LO-Tact-1, respectively (log-rank test, P = 0.57). GVHD contributed to death in four patients who were administered CsA+LO-Tact-1 and in one patient who was administered MTX+CsA+LO-Tact-1. Chronic GVHD occurred in two patients who were treated with CsA+LO-Tact-1 and in two patients treated with MTX+CsA+LO-Tact-1. Throughout therapy, serum levels of LO-Tact-1 ranged from 2 to 10 mg/l. There was no correlation between serum levels of LO-Tact-1 and the occurrence of GVHD. GVHD occurred in 10 patients during LO-Tact-1 prophylaxis. There was no significant difference between relapse or survival rates among the patient groups. We conclude that, while free of adverse effects, monoclonal anti-IL-2 receptor antibody LO-Tact-1 does not improve prophylaxis of GVHD in HLA-matched sibling BMT.

Allogeneic or autologous bone marrow transplantation for acute non-lymphocytic leukemia in first remission.

One hundred and seven consecutive patients with acute non-lymphocytic leukemia (ANL) aged less than 56 years were allocated to receive either allogeneic (allo-BMT) or autologous bone marrow transplantation (auto-BMT) when first complete remission (CR1) was achieved. CR was obtained in 96 patients. Twenty-four patients had an HLA-identical sibling donor and 20 of these (83%) had an allograft in CR1. Thirty-three patients (44% of the CR1 patients without donor) had an autograft in CR1. The reasons for not transplanting patients in CR1 were early relapse (nine patients), refusal (11 patients) or medical problems (23 patients). The 4-year leukemia-free survival (LFS) probability for all the CR1 patients was 25%. For the allo-BMT patients, the 4-year LFS was 71%, and for the auto-BMT patients 31% (log-rank p = 0.028). The relapse probabilities were 33% and 48% respectively (p = 0.40). If the results are analysed according to the intent of the protocol, patients with a donor had an LFS of 53%, and patients without a donor an LFS of 16% (p = 0.003). This study confirms the value of allo-BMT for consolidation of ANL in CR1. The attempt to autograft all CR1 patients without a compatible donor has not resulted in any marked improvement of LFS.

Karyotype in acute myeloblastic leukemia: prognostic significance in a prospective study assessing bone marrow transplantation in first remission.

To evaluate the prognostic value of the karyotype in acute myeloblastic leukemia when patients are allocated to have either autologous bone marrow transplantation (BMT) or allogeneic BMT at the time of first remission (CR1), we have prospectively followed 134 consecutive patients from diagnosis. CR was achieved in 118 patients. Allogeneic BMT and autologous BMT were performed in 25 and 43 CR1 patients, respectively. Applying the karyotype classification of Keating et al for remission duration (favorable: t(15;17), inv(16); intermediate: normal, X -Y, t(8;21); unfavorable: other abnormalities), 10 patients had a favorable, 49 an intermediate, and 44 an unfavorable karyotype. The 5-year leukemia-free survival (LFS) probabilities for patients with a good, intermediate and unfavorable karyotype were 65%, 32% and 11%, respectively (log rank test P = 0.0019). The probabilities of relapse were 35% in patients with a favorable karyotype, 52% with an intermediate karyotype and 87% with an unfavorable karyotype (P = 0.0004). In the patients who had autologous BMT in CR1, the LFSs were 100%, 33% and 10% with favorable, intermediate and unfavorable karyotype, respectively (P = 0.04). The karyotype was of no prognostic value in patients receiving allogeneic BMT who had BMT in CR1. This study shows that the karyotype retains its prognostic value when the intentions is to treat patients with acute myeloblastic leukemia in CR1 with BMT. Autologous BMT was not able to improve the poor prognosis associated with an unfavorable karyotype.