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Researchers describe two cases of patients with chronic myelomonocytic leukemia who developed systemic vasculitis. Vasculitis is an inflammation of blood vessels. This is the first known description of the association between these two diseases.

Acute respiratory failure developed in two patients with hyperleukocytic acute myelomonocytic leukemia with abnormal marrow eosinophils within 1 to 3 days after the beginning of high-dose induction chemotherapy. The presence of moderate pulmonary leukostasis before chemotherapy initiation, the simultaneous occurrence of an acute tumor lysis syndrome, the lack of evidence of any other cause of respiratory distress, and the clinical evolution lead the authors to attribute pulmonary injury to lysis of resident leukemic cells. The responsibility of eosinophilic cellular constituents for the diffuse alveolar damage is discussed. Cancer 1991; 69:1356-1361.

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ [Alpha] Β heterodimers composed of a DQ [Alpha] chain with an arginine at residue 52 ([Arg52.sup.+]) combined to a DQ Β chain lacking an aspartic acid at residue 57 ([Asp57.sup.-]). With the aim of confirming this association, clarifying which heterodimers account for the risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) [Arg52.sup.+] DQ [Alpha]/[Asp57.sup.-] DQ Β heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimers (relative risk [RR] 32, confidence interval [CI] 14.25-71.86, P < [10.sup.-7]). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, CI 17.05-95.5). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P < [10.sup.-7]). 4) The stimulation expression of four different susceptibility heterodimers explains the highest risk of DR3-DQw2/DR4-DQw8 heterozygotes. In conclusion, there is a dose effect of cis- and trans-encoded HLA-DQ [Alpha] Β heterodimers in IDDM susceptibility influenced by the diversity of these molecules. Diabetes 41:378-84, 1992, Insulin-dependent diabetes mellitus (IDDM) results from autoimmune destruction of the insulin-producing Β cells of pancreatic islets. Genetic predisposition to IDDM is partly determined by genes encoded within the MHC, located [...]

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-transretinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P< .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.govas NCT00599937.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

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.

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As2O3). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As2O3-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As2O3-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach.

After completing this course, the reader will be able to: Understand the etiology, symptoms, and impact (as reported by patients) of cancer‐ and chemotherapy‐associated anemia.Recognize the clinical evidence supporting the efficacy of epoetin alfa in reducing transfusion requirements, increasing hemoglobin levels, and improving quality‐of‐life in anemic cancer patients receiving platinum‐ versus nonplatinum‐based chemotherapy.Identify potential prognostic factors for responsiveness to epoetin alfa. Understand the etiology, symptoms, and impact (as reported by patients) of cancer‐ and chemotherapy‐associated anemia. Recognize the clinical evidence supporting the efficacy of epoetin alfa in reducing transfusion requirements, increasing hemoglobin levels, and improving quality‐of‐life in anemic cancer patients receiving platinum‐ versus nonplatinum‐based chemotherapy. Identify potential prognostic factors for responsiveness to epoetin alfa. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Background. Data from two large, community‐based clinical trials that evaluated the efficacy of epoetin alfa in anemic cancer patients receiving chemotherapy were retrospectively analyzed to determine if clinical outcomes were different depending on whether chemotherapy was platinum‐ or nonplatinum‐based. Patients and Methods. Patients received epoetin alfa 150‐300 IU/kg (Glaspy: Study 1; n= 2,342) or 10,000‐20,000 IU (Demetri: Study 2; n= 2,370) s.c. three times each week for 4 months. Efficacy end points were changes in transfusion requirements, hemoglobin (Hb) levels, and quality of life (QOL). A total of 4,298 out of 4,712 patients (platinum‐based, n= 1,601; nonplatinum‐based, n= 2,697), who both received chemotherapy and had available data, were eligible for this retrospective analysis. Results. Baseline characteristics across groups were comparable with few exceptions, which were anticipated in view of the characteristics of the two different chemotherapy types. Decreases in transfusion requirements after 2, 3, and 4 months were significant, regardless of chemotherapy type. Mean increases in Hb level from baseline to final evaluation ranged from 1.6 g/dl to 2.0 g/dl across study groups and were significant, regardless of chemotherapy type. QOL, as measured by the Linear Analog Scale Assessment (LASA), improved significantly by 20%‐43%, regardless of chemotherapy type, and improvements were associated with increases in Hb. Epoetin alfa was well tolerated in both studies, regardless of chemotherapy type. Conclusion. Treatment of anemic cancer patients with epoetin alfa results in significant reduction in transfusion requirements, increase in Hb levels, and improvements in QOL, regardless of whether the chemotherapy is platinum‐ or nonplatinum‐based.

We review improvements achieved in the treatment of acute promyelocytic leukaemia (APL) over the last ten years. The combination of all- transretinoic acid (ATRA) and conventional anthracycline–ARA-C chemotherapy (CT) has clearly demonstrated its superiority over CT alone (in terms of relapse and survival) in newly diagnosed APL. Combination treatment probably also reduces the incidence of initial failures, and complete remission (CR) rates greater than 90% are now regularly reported in large multicentre trials. Some randomized studies strongly suggest than prolonged maintenance treatment (for 1 or 2 years) with ATRA and low dose CT, and possibly very early introduction of anthracycline CT during induction treatment (i.e. not after ATRA) may reduce the incidence of relapse. With those treatments, the risk of relapse appears to be only 10–15%, although it remains greater in patients who initially have white blood cell counts (often associated with variant M3morphology, short bcr3isoform etc.) and patients with residual disease detectable by RT-PCR at the end of consolidation courses.

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA?CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients =75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients =65 years of age and with an initial WBC count of =5,000/µL (n = 208) were randomized between ATRA?CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/µL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA ?CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA?CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA?CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies.

Acute respiratory failure developed in two patients with hyperleukocytic acute myelomonocytic leukemia with abnormal marrow eosinophils within 1 to 3 days after the beginning of high‐dose induction chemotherapy. The presence of moderate pulmonary leukostasis before chemotherapy initiation, the simultaneous occurrence of an acute tumor lysis syndrome, the lack of evidence of any other cause of respiratory distress, and the clinical evolution lead the authors to attribute pulmonary injury to lysis of resident leukemic cells. The responsibility of eo‐sinophilic cellular constituents for the diffuse alveolar damage is discussed. Cancer 1992; 69:1356‐1361.

Seven patients with hairy cell leukemia were treated by intensive chemotherapy because they were considered to have a progressive disease and a poor short-term prognosis. The mean age was 47 years (range, 36 to 58). Six of seven patients had prior splenectomies with minor or transient hematologic responses. One patient had no spleen enlargement. The seven patients had never received any cytotoxic drugs and had prolonged granulocytopenia (< 300/μL) with recurrent, severe infectious episodes. Chemotherapy included Rubidazone (zorubicine hydrochloride) 450 mg/m2on day 1, arabinosyl cytosine 200 mg/m2/d from day 1 to day 5, and cyclophosphamide, 2,000 mg/m2on day 5. Responses were assessed through examination of repeat bone marrow biopsy specimens and blood counts. A complete response was defined as normal blood counts associated with the disappearance of hairy cell infiltration and fibrosis on the bone marrow biopsy specimens. A partial response was defined as normal blood counts with persistence of leukemic cells in the bone marrow. Three patients achieved a complete response, and one patient had a partial response. Three patients died of infectious complications during induction chemotherapy. For the responding patients, the mean duration of aplasia was 37 ± 5 days. Follow-up for the responding patients has been 44+, 24, 32 +, and 23+ months. One patient with a complete response died while on maintenance therapy. We conclude that complete and prolonged histologic remission of hairy cell leukemia can be obtained with intensive chemotherapy. The toxicity of chemotherapy is such, however, that progressive disease after splenectomy needs to be more clearly defined.

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy—skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases—were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

All-trans retinoic acid induces leukemic cells from patients with acute promyelocytic leukemia (M3) to differentiate in vitro to mature granulocytes which express the CD15 antigen and are capable of respiratory burst function. Of 35 M3 samples, only one failed to respond. In eight cases, we compared the efficacy of two naturally occurring isomers of retinoic acid, all-trans RA and 13-cis RA. Both isomers induce maximal differentiation at 10-6mol/L. The maximal response was maintained at 10-7mol/L for the all-trans but not for the 13-cis RA. We also observed that the metabolites 4-oxo-all-trans and 4-oxo-13-cis were effective at 10-6mol/L. This 1 order of magnitude difference in the in vitro differentiating potencies of all-trans RA and 13-cis RA in the blasts of promyelocytic leukemias predicts a difference in the clinical efficacy of the two drugs.

(1) Purpose: To evaluate the therapeutic effect ofall-trans retinoic acid (ATRA) with and without cytosinearabinoside in relapsing malignant gliomas.(2) Patients and methods: 9 patients (8 male,1 female, age 53.9 ± 11.2) with relapsingmalignant gliomas (grade IV:6; grade III:3) were treatedby ATRA 1 to 21 months after theend of their initial treatment. ATRA was givenunceasingly during 2 to 17 months at 90mg/d. In 6 patients it was associated tocytosine arabinoside (4 g/course, 1 to 9 coursesevery 4 weeks).(3) Results: 4 non-responder patients died 2.5 to4 months after starting therapy. One patient whohad been reoperated before receiving ATRA and cytosinearabinoside (5 courses) had no sign of tumorrecurrence after 17 months of treatment. In 4responder patients (2 glioblastoma and 2 anaplastic astrocytoma)a clinical and radiological stabilization (time to progression)during 9 ± 2.5 months was observed. Thisstabilization was associated in 3 of them withthe appearance of intra tumoral calcifications visualized onrepeated CT scans and confirmed in one patientby post-mortem examination. All of them had receivedcytosine arabinoside (1 to 9 courses) with ATRA;however small calcifications were also observed in onenon-responder patient who did not receive aracytine.(4) Conclusion: These results suggest: a) a therapeuticeffect of ATRA in combination with cytosine arabinosidein patients with relapsing malignant gliomas b) thatintratumoral calcifications are related to the effects ofATRA on differentiation and/or on endothelial t-PA productionand that these effects explain the tumor progressionarrest in responder patients. The transient efficiency isprobably related to the pharmacokinetics of ATRA orto changes of cellular mechanisms that modulate thecell response to the drug and is acritical issue for this therapy.

Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia characterized by the morphology of the blast cells, a specific t(15;I7) translocation, and risks of definite coagulopathy. Recently this leukemia was further characterized by an exquisite sensitivity to all‐trans retinoic acid's differentiation effect and the production of a fusion gene altering the gene of RARα and a novel gene PML. In vivo differentiation therapy with retinoids in APL patients follows strict guidelines related both to the APL cell and the biodisposal of all‐Iran retinoic acid.—Chomienne, C., Fenaux, P., Degos, L. Retinoid differentiation therapy in promyelocytic leukemia. FASEB J.10,1025‐1030 (1996)

The clinical, hematologic, and immunologic findings of a syndrome of agranulocytosis, hypogammaglobulinemia, and thymoma are described. Neutrophil agranulocytosis predisposing to severe infectious disease resulted from a defiency of mature cells in bone marrow. Autologous and heterologous stem cell growth in vitro was inhibited by the patient's serum. Immunoglobulin deficiency was secondary to the absence of peripheral blood B lymphocytes, while T-cell subpopulations and cellular immunity were present. Surgical removal of a spindle cell thymoma had no effect on the agranulocytosis and B-cell defiency. The hematologic findings did not respond to steroid therapy and cyclophosphamide. However, the agranulocytosis improved with repeated plasmapheresis and the patient achieved a clinical remission.

Interferons (IFNs) initiate their effects by interacting with specific high-affinity cell surface receptors, but little is known about the physiology of IFN receptor interaction in vivo. Treatment of patients suffering from hairy cell leukemia (HCL) with human recombinant alpha IFN results in significant tumor regression, with clinical improvement in a high percentage of cases. To investigate a possible relevance of binding parameters as response markers, IFN receptor interaction on tumor cells responsive to IFN in vivo was studied. Binding of human alpha 2 IFN to circulating hairy cells was analyzed before and during IFN therapy in ten patients selected on the basis of high numbers of peripheral hairy cells. Binding experiments were carried out on Ficoll-Paque fractionated peripheral cell samples containing a majority of hairy cells. All patients reacted to recombinant alpha IFN treatment with a striking decrease in binding capacity within 12 hours after the first injection. As demonstrated by using a monoclonal antibody able to recognize alpha 2 IFN bound to its receptor, this decreased binding capacity was not due to blocking by circulating IFN but rather to a decrease in receptor number. This receptor “down-regulation” was partially reversible after the first IFN injection. However, upon prolonged IFN therapy, all patients displayed a stable state of decreased receptor expression. Down-regulation of IFN receptors can be regarded as a response marker to IFN treatment. This response marker, however, was not correlated with the clinical response within the first months of IFN therapy.

Seventeen patients with hairy cell leukemia (HCL) were treated with low doses of recombinant alpha interferon (IFN) for over 4 months. Marked improvement was observed in peripheral blood and bone marrow in 15 of 17 patients. Comparison of pretreatment values and nemo-grams obtained after 4 months of treatment showed a marked decrease in circulating hairy cells (P< .01), a decrease in the number of lymphocytes (P< .01), a rise in the number of platelets (P< .05), granulocytes (P< .05), and monocytes (P< .01), and a rise in the hemoglobin level (P< .01). Transient reduction in the number of granulocytes was noted during the first month. Correction of thrombocytopenia often appeared within 2 months and usually preceded improvement of anemia, monocytopenia, and neutropenia. Bone marrow biopsy specimens were taken before treatment and 2, 4, and 7 months after its initiation. The volumes occupied by hairy cells, cells of the myeloid lines, and adipocytes were studied by stereological analysis of semithin sections. Decrease in the volume occupied by hairy cells was seen after 4 months of treatment (P< .01), and the volume continued to decrease at the seventh month (P< .05). Hairy cells were no longer detected on bone marrow biopsies of 4 of 17 patients by the fourth month and in 3 of 8 additional patients by the seventh month. A rise in the volume occupied by normal myeloid cells was visible by the second month of treatment (P< .01). Nevertheless, the volume occupied by granulocytes remained lower than in the normal controls (P< .01). After an initial increase during the first 2 months of treatment (P< .01), the overall cellularity remained unchanged at 4 months and decreased significantly (P< .05) at 7 months. Except for biopsies at 2 months, mean cellularity was below that of control biopsies (P< .01).

BACKGROUND AND DESIGN: Noninfectious cutaneous neutrophilic lesions can occur during granulocytopenia, but their mechanism remains unknown. We undertook a retrospective study of the neutrophilic dermatoses that developed during granulocytopenia induced by chemotherapy for acute myelogenous leukemia. RESULTS: Seven men and one woman were included (2.6% of treated cases of acute myelogenous leukemia); half had acute myelogenous leukemia subtypes 4 and 5. The male-to-female ratio was 7:1. Neutrophilic eccrine hidradenitis was diagnosed in five cases, Sweet's syndrome in two cases, and difficult-to-classify neutrophilic dermatoses in one case. Cutaneous lesions appeared 12.5 days after the start of chemotherapy, and the mean leukocyte count was 0.426× 109/L. Three patients needed corticosteroids systemically. CONCLUSION: Neutrophilic dermatoses during chemotherapy-induced granulocytopenia seem to occur more frequently in men with acute myelogenous leukemia subtypes 4 and 5.(Arch Dermatol. 1995;131:1141-1145)

Acute promyelocytic leukemia (APL) is specifically associated to a t(15; 17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RARα, to a previously unknown gene PML. The PML protein is localized in the nucleus on a specific domain of unknown function (PML nuclear bodies, NB) previously detected with autoimmune sera from patients with primary biliary cirrhosis (PBC). These bodies are nuclear matrix-associated and all of their identified components (PML, Sp100, and NDP52) are sharply upregulated by interferons. We show that autoantibodies against both PML and Sp100 are usually associated in sera with multiple nuclear dot anti-nuclear antibodies and demonstrate that PML is an autoantigen, not only in PBC, but also in other autoimmune diseases. In APL, the PML/RARα fusion interferes with both the retinoic acid (RA) response and PML localization on nuclear bodies, but the respective contribution of each defect to leukemogenesis is unclear. RA induces the terminal differentiation of APL blasts, yielding to complete remissions, and corrects the localization of NB antigens. Arsenic trioxide (As2O3) also induces remissions in APL, seemingly through induction of apoptosis. We show that in APL, As2O3leads to the rapid reformation of PML bodies. Thus, both agents correct the defect in NB antigen localization, stressing the role of nuclear bodies in the pathogenesis of APL.

It has been shown that all-transretinoic acid (ATRA) at doses of 45 to 100 mg/m2/d induces complete remission (CR) of acute promyelocytic leukemia (APL) by a differentiation process. To date, ATRA dose-ranging studies have not yet been evaluated. Thus, we initiated in May 1990 a multicenter study with ATRA at a lower dose of 25 mg/m2/d until CR. Thirty patients with APL were treated with ATRA, of whom 12 were previously untreated, 14 were in first relapse, and 4 had failed after conventional first induction chemotherapy. Twenty-four of 30 achieved CR, 3 failed, and 3 died before day 30. Median time to CR was 45 days. Hyperleucocytosis (14 to 43 × 109white blood cells per liter) was observed in 9 patients between days 10 and 23. Clinical complications that may have been related to the retinoic acid syndrome were observed in 8 patients, of whom 3 died. Pharmacokinetics studies were performed in 5 patients. Peak plasma concentrations and mean area under the concentration-time curve were not lower than previous levels obtained under the 45 mg/m2dose. Overall, our study shows that there is no difference in terms of therapeutic efficacy, triggering of hyperleukocytosis, or retinoic acid syndrome and pharmacokinetic results with ATRA at 25 or 45 mg/m2/d.

IFN-α induces tumor regression with a high percentage of complete remissions in hairy cell leukemia. We have recently reported that hairy cells express specific IFN-α receptors which are down-regulated upon therapy. We show here that the activity of 2–5 A synthetase, an IFN-induced enzyme, is 2 to 7-fold stimulated in hairy cells from responsive patients within 12–24 h after the first IFN dose. This in-vivo enzyme induction paralleled the kinetics of receptor down-regulation. In one patient who was unresponsive to IFN-α treatment neither expression of IFN-α receptor nor change in 2–5 A synthetase could be detected, whereas in a second unresponsive patient, both receptors and 2–5 A synthetase were expressed and modulated as in sensitive patients. In-vitro treatment of hairy cells with recombinant interferons showed that IFN-β1 was able to induce this enzyme to the same extent than IFN-α2, whereas IFN-γ was inactive despite the presence of specific IFN-γ receptors.

Multicentric Castleman's disease (MCD) is an atypical lymphoproliferative disorder defined using clinical and pathologic criteria. A characteristic of the MCD is a close association with Kaposi's sarcoma (KS), which occurs during the clinical course of most human immunodeficiency virus (HIV)-associated MCD cases and also, but less frequently, in HIV-negative patients. Recently, sequences of a putative new Herpesvirus (KSHV) have been isolated and further detected in almost all the acquired immunodeficiency syndrome (AIDS) KS and in most of the non-AIDS KS samples. In this study, we searched for these Herpesvirus-like sequences in MCD samples of 31 patients. KSHV sequences were detected in 14 of 14 cases of HIV-associated MCD, including 5 cases without detectable KS. Moreover, KSHV was detected in 7 of 17 MCD cases in HIV-negative patients, including 1 case associated with a cutaneous KS. In 34 non-MCD reactive lymph nodes (follicular and/or interfoliicuiar hyperplasia) in HIV-negative patients, KSHV was detected in only 1 case. In 1 HIV-negative case of MCD, KSHV was found in both the lymph node and peripheral blood samples. These data suggest that KSHV could play a role in the pathogenesis of MCD, especially in HIV-infected patients.

In subagglutinating amounts, an IgG antibody isolated from the plasma of a polytransfused thrombasthenic patient (L) inhibited ADP-, epinephrine-, collagen-, and thrombin-induced aggregation of normal human platelets. The inhibition of ADP-induced aggregation was strongly diminished following the prior incubation of the antibody with control human platelet stroma but not with the stroma prepared from the platelets of two different thrombasthenic patients. The IgG(L) did not affect the binding of 14C-ADP to control human platelet membranes and did not inhibit the ADP-induced shape change.

Tumor cells from eight adult patients with T-cell chronic malignancies were investigated with a series of monoclonal antibodies recognizing T-cell differentiation antigens. This series allowed definition of discrete subpopulations of mature T cells with functional specialization. All six patients with Sezary syndrome and one patient with T-chronic lymphocytic leukemia had cells with the same phenotype as normal helper/inducer T cells, whereas the other patient with T-chronic lymphocytic leukemia had cells with the same phenotype as normal cytotoxic/suppressor T cells. Some clinical manifestations observed in these patients may reflect retention of functional activities by their malignant cells.

We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) (“events” being defined as failure to achieve complete remission [CR], occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% ± 7% and 50% ±9% at 12 months, respectively, in the ATRA and the chemotherapy group (P= .001). Kaplan-Meier estimate of relapse was 19% ± 8% and 40% ± 12% at 12 months (P= .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.

Richter syndrome is the transformation of chronic lymphocytic leukemia (CLL) into large cell lymphoma. Besides the involvement of lymph nodes, liver, and spleen, bone lesions occur infrequently. We report one case of a patient with a paraspinous mass and destruction of the vertebra by large cell transformation of CLL seen on CT and MRI. There was nothing specific about the clinical presentation, imaging characteristics, and histopathological pattern of bone biopsy that would allow for confident differentiation from infectious spondylitis.

Without Abstract:

A genomic cosmid library constructed from DNA from a genotyped individual (JF = HLA-A11, Cw-, B38/A26, Cw7, B51) was screened for clones containing class I histocompatibility genes. Among these clones, one was found to carry a 4.8 kb Hind III fragment which is highly correlated with HLA-A11. This clone was used to transfect LMTK+ cultured mouse fibroblast transformants expressing human beta-2 microglobulin. The human beta-2 microglobulin heavy chain-associated determinant was positively detected by the M18 monoclonal antibody. HLA-A11 expression on these doubly transformed cells was specifically demonstrated by complement-dependent cytotoxicity with HLA-A11 + A3-specific but not with HLA-A3-specific monoclonal antibodies. Absorption studies with human alloantisera confirmed the presence on these cells of HLA-A11 determinants and of cross-reacting determinants which absorbed anti-HLA-A1 and -A3 alloantisera. The JF5-J27 transfected cell expressed both heavy and light chains of human class I histocompatibility genes.

The first cluster of differentiation (CD1) defines at least three distinct human thymic cell-surface differentiation antigens-CD1a, CD1b, and CD1c. We looked for structural homology of the three CD1 heavy chains at their peptide level by two-dimensional peptide maps. We show here that the CD1a Mr 49 000 heavy chain and the CD1b Mr 45 000 heavy chain appear to be more homologous to each other than to the CD1c Mr 43 000 heavy chain and that only one tyrosil peptide is common to the three heavy chains. Study of the CD1 heavy chains from several individuals reveals a very limited polymorphism of these molecules. We also demonstrate here that CD1a or CD1a-like molecules and other CD1 molecules can form intermolecular complexes on the surface of normal thymus cells. Molecules that are structurally very similar to CD1a molecules are associated noncovalently either with CD1c molecules or with CD1b molecules, and only CD 1a molecules can associate covalently with CD8 molecules. In contrast, we could not find these intermolecular complexes on the surface of leukemic T-cell lines in culture.

H and L inbred mouse strains were derived from animals selected respectively for the production of high and low titers of agglutinins against xenogeneic erythrocytes. L was found to beH-2s. H was found to beH-2Kd,Dq, with anI region derived from another (probably unknown) haplotype.

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbracks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

The presence of two distinct T-cell receptors (TCR) α/β dimers or γ/δ dimers, was systematically analyzed in peripheral blood lymphocytes form 26 recipients of allogeneic bone marrow transplants for leukemia. When using monoclonal antibody WT31, which recognizes a common epitope on the α/βheterodimer, the expansion of peripheral CD3 + , WT31 - cells to 40% of the PBLSs was detected in two patients. In patient 2, the presence of circulating TCRγ-bearing cells was directly demonstrated with monoclonal antibody TiγA directed against the Vγ9 JγP gene products. From CD3 + , WT31 — clones derived from patients 1 and 2, sequential immunoprecipitations were performed with anti-CD3 and anti-Cγ to determine the CD3-associated structure. Molecular weights of γsubunits were different in both patients, thus indicating structural heterogeneity. The ability of TCR7 clones to proliferate when stimulated with anti-CD3 beads was observed for clones from patient 2, whereas this response required exogenous interleukin-2 for clones from patient 1. We have already shown that the TCRγ cells from patient 1 might have played a role in the immunodeficient state. Similar conclusions cannot be drawn from patient 2. Southern blot analysis of total PBL γ cell lines and clones indicated that this major circulating subset of TCRγ cells retained a TCRβ gene in germline configuration and preferentially expressed a single Vγ gene, Vγ5 for patient 1 and Vγ9 for patient 2.© 1988 by Grune & Stratton, Inc. 0006-4971/88/7203-0155$3.00/0

In order to characterize primary anti-HLA cytotoxic T cells and especially those involved in graft rejection, we have utilized a transgenic mouse model. Mice (nontransgenic and HLA-transgenic) were grafted with spleen cells originating from H-2-matched transgenic mice expressing HLA-B27 molecules, and cells from graft-draining lymph nodes were tested in CML assay to investigate the primary in vivo induced CTL responses. The results showed that HLA-B27 molecules were able to raise strong primary xenogeneic CTL responses. Results from split-well analysis indicated that although recognition of HLA-B27 by primary CTL induced in nontransgenic recipients is predominantly unrestricted by H-2, a small fraction (ranging from 2 to 27) of the primary in vivo induced CTL is able to recognize HLA-B27 in an H-2-restricted manner. HLA-specific H-2-restricted CTL had never so far been demonstrated in the primary T cell response. Thus the protocol used in our study for the generation of a primary CTL response seems to provide not only a more appropriate representation of cytotoxic T cells sensitized by a graft, but also to be a more sensitive approach than the usually used in vitro mixed lymphocyte culture.

As a basis for the characterization of mouse T cells involved in the recognition of xenogeneic HLA molecules, a panel of HLA-B27-reactive cytotoxic T-cell clones was generated upon stimulation by cells from HLA-B27-transgenic mice. The HLA-B27-induced T-cell response was found to comprise two categories of clones: some recognizing HLA-B27 independent of H-2 molecules expressed by the target cells (unrestricted clones), others recognizing HLA-B27 in an H-2 restricted manner. The unrestricted clones exhibited diverse specificities, as judged from their various cross-reactivities with other xenogeneic (HLA) or allogeneic (H-2) molecules. In addition, although most of the unrestricted clones were able to react with both mouse and human HLA-B27-transgenic mice. The HLA-B27 induced T-cell which reacted only with HLA-B27-positive mouse, and not human cells. These findings illustrate that both H-2-restricted and unrestricted T cells with diverse species contribute to HLA-B27-xenorecognition.

mRNAs for the two chains of the HLA-DQ molecule were analyzed, in particular the DQa mRNA whose polymorphism had previously been suggested (Schenning et al. 1984). Northern blot transfers of the mRNA of 12 LCLs and of B lymphocytes from a healthy donor were carried out. We report that a length polymorphism of DQa mRNA exists, and we show that it can be correlated with serologically defined specificities (DQwl, DRw53, DR3 + 5). This correlation could be explained by a linkage disequilibrium, as these specificities are considered to be different from those carried by the DQ molecule (except for the DQw1 specificity).

The authors have analyzed the involvement of Vγand Jγsegments in TRGγrearrangement from a series of 40 acute lymphoblastic leukemia (ALL), including 25 T- and 15 B-lineage cases, in which TRGγare rearranged. Sixty-five rearranged alleles were studied. The authors first describe the cloning and sequencing of two variable segments, Vγ11 and ΨVγ12, which rearrange in T- and B-neoplastic cells. To date three subgroups of translatable Vγsegments have been described. The authors show that Vγ11 is the unique member of a new fourth Vγsubgroup that also rearranges in normal polyclonal T cells and that ΨVγ12 is located at 5-kilobase (kb) downstream to Vγ11. As shown by DNA sequence analysis, Vγ11 shares a 60% homology with Vγ10 (third subgroup) and a 50% homology with Vγ9 (second subgroup) but no appreciable homology with the Vγsegments from the first family. In contrast to ΨVγ12, Vγ11 is translatable. In this paper the authors have also attempted to determine which Vγsegments were rearranged in the ALL cases by hybridization with a Jγprobe and genomic probes specific of the four subgroups. In the 54 instances in which the rearrangement was consistent with Jγ1 or Jγ2 involvement, the authors have identified the corresponding Vγsegments and have not found any other rearrangements suggestive of the existence of further V regions. The Vγsegments, belonging to the first subgroup, were the most frequently used (41 alleles). Vγ9, Vγ10, Vγ11, and ↙Vγ12 were found rearranged in cases 3,4, 5, and 1, respectively. No cases using the pseudo ↙Vγ1, ↙Vγ5, and ΨVγ6 segments were found. Pseudo Vγsegments were not found rearranged in T cells, while Vγ2and Vγ4, segments are frequently used. In contrast to the VγI gene rearrangement, the involvement of the VγII, VγIII, and VγIV subgroups was most frequently observed in T-ALL with stage II differentiation (CD7+, CD4+and/or CD8+, CD3-), than in those with stage I (CD7+, CD4-, CD8-, CD3-) and stage III (CD7+, CD4+/-CD8+/-CD3+). Analysis of the involvement of joining segments demonstrated that Jγ1 and Jγ2 were rearranged much more frequently than JγP, JγP1, and JγP2. The analysis of Vγsegment deletions was consistent with rearrangements by loop excision showing the localization of the VγIV subgroup 3‘ to the first, second, and third subgroups and 5‘ to the joining segments. © 1988 by Grune 81 Stratton, Inc.

We entered 26 patients with newly diagnosed acute promyelocytic leukemia (APL) in a pilot study of all-transretinoic acid (ATRA) followed by intensive chemotherapy. Median age was 46 (range 25 to 63). No patient presented with leukocytes >10 × 109/L or had the microgranular APL variant. Cytogenetic analysis (25 patients) found a t(15;17) in 24 cases. Patients were scheduled to receive ATRA (45 mg/m2/d) until complete remission, followed by an intensive daunorubicin (DNR) + Ara C course (“4 + 7” course), then three “2 + 5” DNR + Ara C courses and maintenance chemotherapy. However, the “4 + 7” course was administered in emergency if hyperleukocytosis rapidly developed to prevent leukostasis. Twenty-five patients (96%) achieved CR, 14 with ATRA alone and 11 after the addition of the “4 + 7” course on day 2 to 30 of treatment, because leukocytes rapidly increased (9 cases), because of resistance to ATRA (1 case), and development of organomegaly (1 case). The remaining patient died on day 6, from CNS bleeding. Apart from hyperleukocytosis, side effects were usually moderate. In the 11 patients who could be studied in vitro, a very good correlation was found between in vivo and vitro differentiation and proliferation of APL blasts with ATRA. Three patients were allografted after the “4 + 7” course. Four patients did not receive this course but received the subsequent “2 + 5” courses and maintenance. The remaining patients followed the scheduled protocol. Three patients relapsed after 8, 11, and 15 months (including one allografted patient). Two patients died in CR, after 6 and 17 months. The other 20 patients remained in CR after 18+to 34+ months (median 21). Actuarial disease free interval (DFI) and event free survival (EFS) were 87% and 77%, respectively, after 18 months. These results were compared to those obtained in our previous APL 84 trial with chemotherapy alone in newly diagnosed APL (after excluding patients included in this trial who presented with hyperleukocytosis). In APL 84 trial, the CR rate was 76%, the actuarial DFI and EFS were 59% and 48% after 18 months, respectively. Differences with the pilot study of ATRA followed by chemotherapy were significant for DFI (P= .02), EFS (P= .006), but not for CR rate (P= .08). Although this is a historical comparison, these results suggest that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, by slightly increasing the CR rate, but perhaps more importantly by reducing the relapse rate. This question is now being addressed to in a multicenter trial randomizing between the two therapeutic approaches in newly diagnosed APL.