[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.

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.

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.

Skeletal survey in advanced multiple myeloma: radiographic versus MR imaging survey.

In an attempt to compare the sensitivity of bone radiographs and bone marrow magnetic resonance (MR) imaging for bone lesion detection in patients with stage III multiple myeloma (MM) and to evaluate the possible consequences of the replacement of the conventional radiographic skeletal survey (RSS) by an MR survey of the spinal and pelvic bone marrow in these patients, we obtained MR studies of the thoracic and lumbar spine, pelvis and proximal femurs in addition to the conventional RSS (including radiographs of the skull, entire spine, pelvis, ribs, humerus and femurs) in 80 consecutive patients with newly diagnosed stage III MM according to the Durie and Salmon staging system (based on blood tests and on the RSS). The performance of MR and radiographic studies to detect bone lesions in given anatomic areas and in given patients were compared. The consequences on MM staging following the substitution of the RSS by the MR survey were assessed. MR imaging was superior to radiographs for lesion detection in the spine (76% v 42% of patients) and pelvis (75% v 46% of patients). The RSS was superior to the limited MR imaging survey for the detection of bone involvement in the patient population (87.5% v 79% of patients). If the RSS had been replaced by the MR imaging survey for patient staging, 7/80 patients would have been categorized as stage I and one as stage II MM on the basis of normal MR findings and biological findings consistent with these stages. Substitution of the RSS by a limited spinal and pelvic marrow MR survey would lead to 'understaging' of 10% of patients with otherwise stage III MM on the basis of blood tests and the conventional RSS.

Myelodysplastic syndrome with monosomy 5 and/or 7 following therapy with 2-chloro-2'-deoxyadenosine.

A few cases of secondary neoplasms occurring after treatment with 2-chloro-2'-deoxyadenosine (2CdA) have been reported, mostly in patients previously exposed to other anti-cancer drugs including alkylating agents (AA). Here we report on the occurrence of a myelodysplastic syndrome (MDS) with monosomy 5 and/or 7 in two patients after 2CdA treatment, without or prior to other toxic exposure. In light of a literature review and given the involvement of chromosomes frequently abnormal in secondary leukaemias, we suggest that 2CdA may induce therapy-related MDS (t-MDS).

Stage III multiple myeloma: clinical and prognostic value of spinal bone marrow MR imaging.

PURPOSE: To determine the clinical and prognostic value of spinal bone marrow magnetic resonance (MR) imaging in stage III multiple myeloma. MATERIALS AND METHODS: In 80 patients with untreated, newly diagnosed stage III multiple myeloma, initial MR imaging patterns of spinal bone marrow involvement were correlated with hematologic parameters and response to induction chemotherapy. The influence of these patterns on survival was studied in 57 patients who did not undergo cytotoxic therapy with stem cell transplantation. RESULTS: MR imaging patterns of marrow involvement were normal in 19 (24%) patients, focal in 35 (44%), and diffuse in 26 (32%). Patients with the diffuse pattern had higher marrow plasmacytosis (P < or = .003) and cellularity (P < or = .001), higher serum calcium (P < or = .005) and beta 2-microglobulin (P < or = .008) levels, and lower hemoglobin values (P < or = .001) than did those with the normal or focal patterns. Patients with the normal pattern responded better to therapy (P = .007) and survived longer than patients with an abnormal pattern (P = .026). MR imaging findings and C-reactive protein level were the best independent prognostic indicators of survival. CONCLUSION: MR imaging patterns of spinal bone marrow involvement are correlated with several clinical parameters of disease severity and have prognostic value in stage III multiple myeloma.

VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85).

263 patients (median age 65+/-10 years) with multiple myeloma were treated with cyclophosphamide-prednisone. Out of this cohort, 103 patients had progressive disease and were randomly assigned to either VAD (vincristine, doxorubicin, dexamethasone; 50 cases) or VMBCP (vincristine, BCNU, cyclophosphamide, melphalan and prednisone; 53 cases). There were no statistical differences between the two groups with the respect to clinical, biological and radiological parameters. There was no difference in survival between the VAD and VMBCP groups. The 4 months response rate was similar in the two groups (50% VAD, 56% VMBCP). With multivariate analysis for survival (Cox model), two factors had a statistically significant impact: Karnofsky index (> 60) and albuminaemia (< 34 g/l). With both Karnofsky index > 60 and albuminaemia > or = 34 g/l, the median survival was 29 months v 2 months with a Karnofsky index < or = 60 and albuminaemia < 34 g/l (P<0.05). In conclusion, VAD or VMBCP had similar activity for salvage treatment in MM refractory or relapsing to first-line treatment with cyclophosphamide-prednisone.

Chronic lymphocytic leukemia: changes in bone marrow composition and distribution assessed with quantitative MRI.

The purposes of this study were (a) to determine the prevalence of bone marrow abnormalities in patients with chronic lymphocytic leukemia (CLL) using quantitative MR assessment of axial marrow composition and peripheral marrow distribution; (b) to assess the agreement between both quantitative MR methods and compare their sensitivities to detect marrow alterations; and (c) to correlate MR findings with clinical and laboratory parameters. Twenty-nine consecutive patients with biopsy-proven CLL were investigated on a .5-T MR imager to determine bulk T1 relaxation times of the vertebral bone marrow and proportion of proximal femur surface area occupied by nonfatty marrow on coronal T1-weighted MR images of one hip. Of the 29 patients, 12 (41%) had abnormal increase in lumbar marrow T1 values (>600 msec) and 16 (55%) had increased proportion of surface area occupied by nonfatty marrow in the proximal femur (>+1 SD compared to normal values determined in sex- and age-matched healthy subjects). The results of both quantitative MR methods were normal in 12 patients and abnormal in 11 patients (agreement, 79%). Patients with alterations in peripheral marrow distribution had significantly higher T1 relaxation times (P = .001) than those with normal peripheral marrow. Patients with abnormal marrow composition or distribution at MRI had significantly higher blood and marrow lymphocytosis than patients without these features. In conclusion, the agreement between both quantitative MR methods suggests a parallelism between changes in axial marrow composition and in peripheral marrow distribution in patients with CLL. The limits of quantitative MRI in CLL must be kept in mind, because quantitative MR methods failed to detect leukemic marrow infiltration in 41% of patients.

2-Chlorodeoxyadenosine with or without daunorubicin in relapsed or refractory acute myeloid leukemia.

2-Chlorodeoxyadenosine (2-CdA) is a purine analogue which has proved to be active in acute myeloid leukemia (AML), especially in children. In adults, results yielded by 2-CdA alone or with ara-C were less encouraging. Here we report on the efficacy of 2-CdA with or without daunorubicin (DNR) in 19 relapsing or refractory adult AML patients, with a median age of 57 years. 2-CdA was administered as a continuous infusion to all patients at a dose of 0.1 mg/kg per day for 7 days. For 14 patients, DNR was added at a dose of 50 mg/m2 per day on days 5, 6, and 7. Antileukemic activity was observed in all the patients, but no single complete remission was achieved. One patient had a long-lasting partial response (response rate=5%). The remaining patients died of progressive AML (n=7), uncontrollable infection with persistent disease (n=10), and cerebral hemorrhage (n=1). Median survival from start of 2-CdA therapy was 56 days. Long-lasting neutropenia and transfusion-dependent thrombopenia were encountered in all 16 evaluable patients. Grade 4 hepatic toxicity occurred in one patient. Other side effects included nausea in six, mucositis in three, and mental disturbances in three patients. Compared with 2-CdA alone, the addition of DNR to 2-CdA changed neither the response rate nor the toxicities. In conclusion, our data do not support the use of 2-CdA +/- DNR for relapsing or refractory adult AML patients, at least as used in the present regimen.

Early chronic lymphocytic leukemia: prognostic value of quantitative bone marrow MR imaging findings and correlation with hematologic variables.

PURPOSE: To determine the frequency of abnormal findings from quantitative bone marrow magnetic resonance (MR) imaging in patients with early-stage chronic lymphocytic leukemia, to correlate these findings with clinical parameters, and to compare spontaneous outcome in patients with normal or abnormal MR imaging findings. MATERIALS AND METHODS: In 21 patients with Binet stage A (Rai stage 0-I) disease, bulk T1 values of the vertebral bone marrow were determined and correlated with initial clinical, laboratory, histopathologic, and cytogenetic findings and with treatment-free survival. RESULTS: Bulk T1 values were normal (< 600 msec) in 14 patients and prolonged in seven. Patients with increased T1 had significantly higher blood (P = .017) and bone marrow (P = .015) lymphocytosis. None of the 14 patients with normal T1 values required specific therapy after a median follow-up of 13 months. Of the seven patients with abnormal T1 values, five required treatment after progression to Binet stage B or C disease at a median of 10 months. CONCLUSION: In patients with abnormal quantitative MR imaging findings, treatment-free survival appears to be significantly shorter (P < .001) than in patients with normal MR imaging findings.

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.

Vertebral compression fractures in multiple myeloma. Part II. Assessment of fracture risk with MR imaging of spinal bone marrow.

PURPOSE: To determine the utility of bone marrow magnetic resonance (MR) imaging in the assessment of risk of vertebral compression fractures in patients with multiple myeloma. MATERIALS AND METHODS: In 50 patients with stage III multiple myeloma, 280 MR examinations of the thoracolumbar spine obtained at diagnosis and during treatment (mean follow-up, 28 months) were analyzed to determine MR patterns of bone marrow involvement before treatment and the occurrence of vertebral compression fracture at follow-up. Four MR patterns of marrow involvement were determined: A, normal marrow appearance; B, fewer than 10 focal lesions; C, more than 10 focal lesions; and D, diffuse infiltration. Fracture-free survival was compared according to these patterns. RESULTS: During follow-up, 131 vertebral compression fractures appeared in 37 patients. Patients with pattern A (n = 10) or B (n = 16) had significantly longer fracture-free survival before occurrence of the first, second, and third fractures than those with pattern C or D (P < 10(-5)). Relative risks of first, second, and third fracture occurrence for patients with pattern C or D compared with those with pattern A or B were 6.2, 9.1, and 11.0, respectively. CONCLUSION: Determination of MR patterns of spinal bone marrow involvement is a potential relevant factor to predict the risk of vertebral fractures in patients with stage III multiple myeloma.

Vertebral compression fractures in multiple myeloma. Part I. Distribution and appearance at MR imaging.

PURPOSE: To study the appearance and distribution of vertebral compression fractures on magnetic resonance (MR) images in patients with multiple myeloma. MATERIALS AND METHODS: Two hundred twenty-four vertebral compression fractures were studied on 216 sagittal T1-weighted spin-echo and T2*-weighted gradient-echo MR images of the thoracolumbar spine obtained before and during treatment in 37 patients with multiple myeloma. Vertebral compression fractures observed at diagnosis and during follow-up were determined as being benign- or malignant-appearing at MR imaging according to literature criteria, and their distribution along the spine was recorded. RESULTS: One hundred forty-nine (67%) of the 224 vertebral compression fractures appeared benign; 75 (33%) appeared malignant. Of the 37 patients, 14 (38%) had only benign-appearing vertebral compression fractures at diagnosis. One hundred five fractures (87%) were observed between T-6 and L-4, and 112 (50%) occurred between T-11 and L-3. Eight (4%) vertebral compression fractures involved the upper three thoracic vertebrae. CONCLUSION: Most vertebral compression fractures in patients with multiple myeloma appear benign at MR imaging, and their distribution is similar to that observed in osteoporotic fractures. The possibility of multiple myeloma should not be excluded in patients with benign-appearing vertebral compression fractures at MR imaging.

Pericarditis induced by high-dose cytosine arabinoside chemotherapy.

Pericarditis is a rare side effect of chemotherapy. We report here the case of a patient treated with high-dose cytosine arabinoside (HD ara-c) who developed severe pericarditis. Interruption of HD ara-c and initiation of corticosteroid treatment were effective in resolving the pericardial effusion. This case illustrates this rare but potentially life-threatening cardiac complication of HD ara-c therapy as well as the beneficial effect of corticosteroid treatment.

Long-term effects of localized spinal radiation therapy on vertebral fractures and focal lesions appearance in patients with multiple myeloma.

The occurrence of new vertebral fractures and focal marrow lesions was determined and compared in irradiated and nonirradiated vertebrae of 12 patients with multiple myeloma (MM), prospectively followed using magnetic resonance imaging (MRI) of the thoraco-lumbar spine after localized spinal radiation therapy. During follow-up (mean 35 months), fractures appeared in 5% of irradiated vertebrae and in 20% of nonirradiated vertebrae: new focal lesions appeared in 4% of irradiated vertebrae and in 27% of nonirradiated vertebrae. This study demonstrates a beneficial long-term effect of localized radiation therapy, consisting of a reduced incidence of vertebral fractures and focal marrow lesions in irradiated vertebrae.

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.

Recirculated normal platelets adhere to surfaces coated with plasma from patients with immune thrombocytopenia.

Immune thrombocytopenic purpura (ITP) patients have characteristic anti-platelet antibodies in their circulation. To assess the interaction between such antibodies adhering on to a non-physiological surface and human platelets, normal anticoagulated blood was perfused over ITP patient plasma-coated surfaces in a parallel plate flow chamber. At 300 s-1, platelet adhesion to patient plasma-coated glass coverslips (24.0 +/- 10%) was significantly higher than the adhesion to normal plasma-coated surfaces (9.8 +/- 7%). When perfused at 1300 s-1, the adhesion to patient plasma-(5.1 +/- 1.3%) and to normal plasma-(2.5 +/- 1.2%) coated coverslips were significantly weaker. Furthermore, patient platelet binding depended on simultaneous contributions by antibodies and fibrinogen present on the plasma-coated surface, since adherence was antagonized both by normal immunoglobulins added to the perfusate, as well as by the anti-GPIIb/IIIa monoclonal antibody 16N7C2, which competes with fibrinogen for binding to its receptor on the platelet. Accordingly, platelet adhesion was only observed to coverslips coated with the plasma but not the serum of ITP patients. Hence, perfusion of normal platelets over surfaces coated with ITP patient plasma enables a functional assessment of the presence in this plasma of anti-platelet antibodies.

Nonmyelomatous monoclonal gammopathy: correlation of bone marrow MR images with laboratory findings and spontaneous clinical outcome.

PURPOSE: To determine the frequency of abnormal bone marrow magnetic resonance (MR) images in patients with nonmyelomatous monoclonal gammopathy and to compare the outcomes in patients with normal and in those with abnormal MR studies. MATERIALS AND METHODS: In 37 patients with monoclonal gammopathy of undetermined or borderline significance (19 men, 18 women; aged 28-85 years), MR imaging findings of the vertebral, pelvic, and femoral bone marrow were analyzed and correlated with initial laboratory findings and outcome after a follow-up of 15-60 months (median, 31 months) with no treatment. RESULTS: Thirty patients had normal MR studies; none required specific therapy after a median follow-up of 30 months. Seven had either diffuse (n = 4) or focal (n = 3) bone marrow abnormalities. Four required treatment after 15, 20, 50, or 58 months; three did not require treatment after 18, 26, or 40 months. Treatment-free survival curves in patients with normal and in those with abnormal MR studies were statistically significantly different (P = .005). CONCLUSION: Bone marrow abnormalities were detected with MR imaging in seven patients (19%) with monoclonal gammopathy of undetermined or borderline significance. All patients with a normal MR investigation still had not required treatment after a median follow-up of 30 months.