Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention.

To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age

Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group.

PURPOSE: To analyze clinical outcome and significant prognostic factors for overall (OS) and time to treatment failure (TTF) in a group of 494 patients with Hodgkin's disease (HD) undergoing autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Detailed records from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group Database on 494 HD patients who received an ASCT between January 1984 and May 1998 were reviewed. Two hundred ninety-eight males and 196 females with a median age of 27 years (range, 1 to 63 years) received autografts while in complete remission (n = 203) or when they had sensitive disease (n = 206) or resistant disease (n = 75) at a median time of 26 months (range, 4 to 259 months) after diagnosis. Most patients received high-dose chemotherapy without radiation for conditioning (n = 443). The graft consisted of bone marrow (n = 244) or peripheral blood (n = 250). RESULTS: The 100-day mortality rate was 9%. The 5-year actuarial TTF and OS rates were 45.0% (95% confidence interval [CI], 39.5% to 50.5%) and 54.5% (95% CI, 48.4% to 60.6%), respectively. In multivariate analysis, the presence of active disease at transplantation, transplantation before 1992, and two or more lines of therapy before transplantation were adverse prognostic factors for outcome. Sixteen patients developed a secondary malignancy (5-year cumulative incidence of 4.3%) after transplantation. Adjuvant radiotherapy before transplantation, the use of total-body irradiation (TBI) in the conditioning regimen, and age > or = 40 years were found to be predictive factors for the development of second cancers after ASCT. CONCLUSION: ASCT achieves long-term disease-free survival in HD patients. Disease status before ASCT is the most important prognostic factor for final outcome; thus, transplantation should be considered in early stages of the disease. TBI must be avoided in the conditioning regimen because of a significantly higher rate of late complications, including secondary malignancies.

Prolonged survival after liver transplantation for Hodgkin's disease-induced fulminant liver failure.

A 30-year-old male with a past history of nodular lymphocyte predominance Hodgkin's disease in apparent complete remission for two years received a liver transplantation because of fulminant liver failure. Histopathological examination of the explanted liver showed massive infiltration by Hodgkin's disease. In spite of a nodal recurrence of Hodgkin's disease, the patient is alive and in excellent general condition six years after liver transplantation.

Autologous peripheral blood stem cell transplantation for multiple myeloma: a report of 259 cases from the Spanish Registry. Spanish Registry for Transplant in MM (Grupo Español de Trasplante Hematopoyético-GETH) and PETHEMA.

Between January 1989 and November 1995, 259 patients with multiple myeloma (MM), 22 stage I, 57 stage II and 180 stage III at diagnosis were treated with myeloablative high-dose therapy followed by autologous peripheral blood stem cell (PBSC) transplantation. The median time from diagnosis to transplantation was 17 months (6-112). At the time of transplant, 56 patients were in CR, 153 in PR, 25 were nonresponders and 25 had progressive disease. Mobilization of stem cells was performed with G-CSF alone in 141 cases, chemotherapy plus G-CSF in 65, chemotherapy plus GM-CSF in 36 and chemotherapy alone in 17 patients. The conditioning regimen consisted of high-dose melphalan alone in 96 patients, melphalan plus TBI in 73, busulfan plus melphalan in 56, busulfan plus cyclophosphamide in 27 and cyclophosphamide plus TBI in seven. The median durations of neutropenia (>0.5 x 10(9)/l) and thrombocytopenia (>20 x 10(9)/l) were 12 (5-118) and 13 days (5-360), respectively. Transplant-related mortality occurred in 11 patients (4%). Once a stable graft was achieved, 114 patients (44%) received maintenance treatment with recombinant alpha interferon (IFN-alpha). Among the 248 patients evaluable for response 125 (51%) had a CR and 100 had a PR (40%). The median duration of progression-free survival (PFS) and overall survival (OS) after transplantation was 23 and 35 months, respectively. Univariate analysis showed that response status pretransplant, only one line of primary induction treatment and IFN-alpha maintenance treatment post-transplant significantly influenced OS. Female sex, pretransplant responsive disease, and treatment with IFN-alpha post-transplant were the factors significantly influencing PFS. The conditioning regimen and method of stem cell mobilization had no significant impact on OS and PFS. On multivariate analysis the only independent factors associated with a longer survival were the number of chemotherapy courses prior to autologous PBSC transplantation and the pretransplant response status. The present analysis from the Spanish Registry confirms the feasibility of autologous PBSC transplantation in myeloma patients with a very low toxicity (4% toxic deaths). The high complete response rate after transplantation is encouraging. The best results are obtained when the procedure is performed early after the first line of induction therapy and in patients with chemosensitive disease. Whether early high-dose therapy followed by autotransplantation in responding patients is superior to conventional chemotherapy is currently being investigated in prospective randomized studies.

Are myeloma patients with renal failure candidates for autologous stem cell transplantation?

INTRODUCTION: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insufficiency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. MATERIALS AND METHODS: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were defined: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. RESULTS AND CONCLUSION: Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).

Predominance of gram-positive microorganisms as a cause of septicemia in patients with hematological malignancies.

OBJECTIVE: To ascertain the etiology and outcome of episodes of bacteremia and fungemia over a three-year period (1990-1992) in patients with hematological malignancies. DESIGN: Retrospective study. SETTING: Hematology service of a 1,500-bed Spanish university hospital. RESULTS: Of a total of 178 episodes of significant bacteremia or fungemia in 101 patients, 53% affected patients with acute leukemia. Gram-positive microorganisms were found to be the cause in 70% of the monomicrobial episodes. The most frequently isolated microorganism was coagulase-negative Staphylococcus (35%), followed by Staphylococcus aureus (11%). Most blood-stream infections occurred during an episode of neutropenia (59%). A total of 34 patients died during hospitalization; in 14, infection was the cause of death. CONCLUSIONS: A marked increase in the incidence of bacteremias caused by gram-positive microorganisms has been observed in our hospital over the last 10 years, especially in patients with hematological malignancies. The mortality due to bacteremia is similar to that found by other authors in series of bacteremia in hematological patients, and we have not found significant differences in the mortality due to bacteremia between neutropenic and non-neutropenic patients (Infect Control Hosp Epidemiol 1994;15:101-104).

Idarubicin and intermediate dose ARA-C followed by consolidation chemotherapy or bone marrow transplantation in relapsed or refractory acute myeloid leukemia.

Sixty-one adult patients with relapsed or refractory acute myelogenous leukemia (AML) were treated in a cooperative study with Idarubicin 12 mg/m2/day on days 1 to 3 and AraC 1 g/m2/12h on days 1 to 4. Responding patients were scheduled for consolidation with Ida-IDAraC and bone marrow transplantation (BMT) when feasible. Twelve of 23 refractory patients (52%) and 21 of 38 relapsed patients (55%) achieved complete remission (CR). Refractory patients treated very early with Ida-IDAraC (CR 63%) and relapsed patients with initial CR > 6 months (CR 68%) were the subgroups with better CR rate. The only factor influencing the disease free survival (DFS) was the intensity of postremission therapy: Nine patients had severe toxicity with the salvage regimen and were excluded for consolidation, fourteen patients received Ida-IDAraC and ten patients proceeded to myelo-ablative therapy supported with autologous or allogeneic BMT. The three groups had different median DFS of 6 months, 9 months and 15 months respectively (P = 0.017). In summary, Ida-AraC is an efficient salvage regimen for AML. The CR rate seems to be improved in refractory patients if used promptly, but the long term outcome appears to depend on the intensity of treatment given once remission is achieved and on the ability to perform BMT.

Autotransplantation of peripheral blood stem cells mobilized by G-CSF in hematological malignancies: evidence for rapid and long-term sustained hematopoietic reconstitution.

We assessed the ability of granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSC), the efficacy of PBSC infusion in the rescue of hematopoiesis after high-dose chemotherapy in 22 adult patients with hematological malignancies, and the long-term quality of engraftment. Bolus subcutaneous injections of G-CSF (12 micrograms/kg/day) were administered for 6 days. A median of three leukaphereses resulted in the collection of a median of 5.45 X 10(8) mononuclear cells/kg, 4.52 X 10(6) CD34+ cells/kg, and 3.97 X 10(4) CFU-GM/kg. G-CSF (5 micrograms/kg daily) was administered after PBSC infusion until granulocyte recovery. The median time to attain a neutrophil level > 0.5 X 10(9)/L and a platelet count > 20 X 10(9)/ L was 11 days. The median follow-up in 17 survivors was 23.8 months. These patients have maintained a complete and stable graft and some of them with neoplastic recurrence tolerated further chemotherapy. These results confirm that mobilization of PBSC by G-CSF can be performed on an outpatient setting and used in heavily pretreated patients. G-CSF mobilized PBSC transplantation provides early and complete engraftment in most patients.

[Infectious complications in neutropenic patients with malignant hemopathies. A prospective study of 279 cases of neutropenia]. / Complicaciones infecciosas en pacientes neutropénicos con hemopatías malignas. Estudio prospectivo de 279 episodios de neutropenia.

We prospectively evaluated the infective complications in 279 neutropenic episodes which developed during the treatment of 79 patients with malignant hemopathies over a 35 month period. In 150 episodes (53.73%) infections were detected: one infection in 121 episodes and two in 29 episodes. Overall 179 infections were detected. 75 of them (41.89%) were considered as possible, 57 (31.84%) were microbiologically documented with bacteremia/fungemia 24 (13.40%) were clinically documented, and 23 (12.84%) were microbiologically documented without bacteremia/fungemia. The portal of entry could not be identified in 121 infections (67.59%), 26 (14.76%) originated in the skin and soft tissues, 14 (7.82%) in the lung, 7 (3.91%) in the oropharynx, 5 (2.79%) in a catheter, and 6 (3.33%) were of miscellaneous origin. Of 80 microbiologically documented infections, 39 (48.75%) were due to gram-negative bacteria, 23 (28.75%) to gram-positive bacteria, 12 (15%) to fungi, and 6 (7.5%) to polymicrobial flora. The overall mortality rate was 4.3%. It was 8% for episodes complicated by infection and 0 in episodes of neutropenia without infection.

[The use of 125I-fibrinogen in the diagnosis of deep venous thrombosis in medical practice (author's transl)]. / El uso del fibrinógeno-125I en el diagnóstico de la trombosis venosa profunda en clínica médica.

A series of 38 "high risk" selected cases of deep venous thrombosis were studied in an internal Medicine Department. Fibrinogen-125I was used. Phlebographic verification was sought in those cases with a positive response to the fibrinogen. From the 38 cases 13 turned out to be positive; in 8 the venous thrombus was identify by venography. In two cases the dorsal venous arch could not be filled. In one case the phlebography could not be carried out. In the remaining two cases the venography did not show a thrombus but there was a pathologic fracture with hematoma and an ossifying myositis, respectively. Both cases were interpreted as false positives to the radioactive fibrinogen. One of them had suggestive clinical manifestations of deep venous thrombosis. Of the eight cases which were positive to the venography and radioactive fibrinogen only four showed a clinical picture suggestive of deep venous thrombosis. If the three cases with negative venographies are included only 36.3 percent of the patients had clinical manifestations. Among the 25 cases which were negative to the radioactive fibrinogen none of them had a clinical picture of deep venous thrombosis, although in 64 percent of them at least one of the clinical signs collected during the physical examination was positive. The correlation between fibrinogen-125I and phlebography turned out to be 80 percent.

[Non-Hodgkin's lymphomas associated with the acquired immunodeficiency syndrome. A multicenter clinical study of 77 cases]. / Linfomas no hodgkinianos asociados al síndrome de la inmunodeficiencia adquirida. Estudio clínico multicéntrico de 77 casos.

BACKGROUND: The aim of the present was to study the prevalence of non Hodgkin's lymphoma (NHL) in AIDS patients as well as the clinicopathologic characteristics, response to treatment and survival. METHODS: From January 1984 to January 1991, 77 patients with NHL associated with AIDS diagnosed in 9 hospitals in Madrid were retrospectively studied. RESULTS: Ninety-two per cent of the patients were men (mean age 30 years: range: 9-66 years), 62% were intravenous drug abusers and 20 (26%) homosexuals. Pathologic study determined that 62 (80%) patients had high grade NHL (44% small noncleaved), 17% immunoblastic and 20% unclassifiable, and 15 (20%) had intermediate grade (16% diffuse large cell) being all the cases of the B immunophenotype. Sixty-five per cent were in advanced stages and 69% had B symptoms. Extranodal localizations were present in 88%, bone marrow in 29% and CNS in 29%. Six cases had primary CNS lymphomas. 50% of the patients had less than 200 x 10(6)/l CD4 lymphocytes. Forty-seven patients were evaluable for response to chemotherapy: 12 (26%) showed a complete response 27 (57%) a partial response and 8 (17%) did not respond. Opportunistic infections developed in 18%. The estimated survival at 3 years was 14% (median 6 months). On univariate analysis the parameters related to the worst survival were: primary CNS lymphoma, liver involvement, lack of treatment response, LDH > or = 300 UI/l, alkaline phosphatase > or = 500 UI/l and ESR > or = 70 mm. CONCLUSIONS: Non Hodgkin's lymphomas associated with AIDS usually behave in an "aggressive" way with a high frequency of advanced stages, B symptoms, high grade histologic subtypes and extranodal involvement. Response to treatment is poor, bone marrow toxicity frequent and survival short.

[PCR study of bcl-2 rearrangement in autologous transplantation of peripheral stem cells in follicular non-Hodgkin's lymphoma]. / Estudio por PCR del reordenamiento bcl-2 en el trasplante autólogo de células progenitoras de sangre periférica en el linfoma no hodgkiniano folicular.

OBJECTIVE: To value the usefulness of the bcl-2 rearrangement analysis by PCR in the study of the minimal residual disease in patients with follicular non-Hodgkin's B cell lymphoma (NHL) submitted to peripheral blood stem-cell transplantation (PSCT). PATIENTS AND METHOD: The study was done on 12 patients diagnosed with low grade B-cell NHL, who were entered in a program of myeloablative chemotherapy followed by rescue with progenitor cells obtained from peripheral blood. At the time of peripheral stem-cells (PSC) harvesting, 8 patients did not present medullar infiltration and four of them presented medullar infiltration according to conventional histological criteria. The study was done on DNA from samples taken from bone marrow and cells taken in the apheresis. The DNA samples were studied by PCR to determine the existence of the bcl-2 rearrangement. RESULTS: At the time of apheresis, 8 patients did not present medullar infiltration according to conventional histological criteria but 7 of them presented bcl-2/JH rearrangement. Most patients studied (10 out of 12) showed bcl-2/JH rearrangement (minimal residual disease) in apheresis products. However, in 2 of these 10 patients, such rearrangement was negative in the bone marrow samples obtained 3-6 and 12 months after transplantation. CONCLUSION: In some patients with follicular NHL submitted to PSCT, the bcl-2/JH rearrangement had negativized after transplantation, this implies that the tumoral cells present in apheresis products lost their clonogenic capacity and were not able to subsist in vivo and that the myeloablative polychemotherapy schedules are able to eradicate the t(14; 18) translocation bearing cells or, at least, to decrease their number in bone marrow to levels below those of PCR detection.

[Remission induction treatment in adults with acute myeloid leukemia. 8-year experience with 2 successive protocols]. / Tratamiento de inducción la remisión en adultos con leucemia aguda mieloide. Ocho años de experiencia con dos protocolos sucesivos.

We report our eight year experience remission induction therapy in adult patients with acute myeloblastic leukemia. Overall 67 patients were treated, with a mean age of 43.3 years (range 15-75). Two treatment protocols were used. Complete remission (CR) was achieved in 23 patients of 39 receiving protocol A (58%). The 28 last patients were treated with the more aggressive protocol B, and CR was achieved in 23 patients (82%). CR was achieved in 68% of the overall group. The most outstanding predictive factors were age above 30 years, and M-5 morphology as indicating a poor prognosis.

[The relationship between the persistence of the BCR/ABL gene and relapse in adult patients with acute lymphoblastic leukemia]. / Relación entre la persistencia del gen BCR/ABL y la recaída en pacientes adultos con leucemia linfoblástica aguda.

BACKGROUND: The Philadelphia chromosome (Ph') is originated by the t(9;22) which determines the rearrangement BCR/ABL. This rearrangement has been associated with an unfavourable prognosis in patients diagnosed with adult acute lymphoblastic leukaemia (ALL). PATIENTS AND METHODS: The BCR/ABL gene (p210 and p190) was prospectively studied by nested RT-PCR in 17 adult patients diagnosed with ALL BCR/ABL-positive cases were monitored by RT-PCR and cytogenetic techniques over the treatment period (LAL-93 AR protocol). RESULTS: BCR/ABL mRNA was detected in 8 out the 17 patients studied (47%). The Ph' chromosome was detected in 4 cases. Follow-up was completed in 6 out of the 8 BCR/ABL positive cases. PCR only became negative in one patient. The 5 patients with persistently positive BCR/ABL relapsed, whereas the case which became negative was still in complete remission after 24 months follow-up. In 3 out of the 4 Ph' positive patients, the karyotype was normal after induction therapy. CONCLUSIONS: This study clearly demonstrates the usefulness of molecular analysis in the diagnosis and follow-up of ALL compared with conventional cytogenetic techniques. The importance of molecular analysis to assess the efficacy of the treatment used has been emphasized and the poor evolution of BCR/ABL-positive patients has been confirmed.

[Complete remission without marrow aplasia phase in a patient with acute promyelocytic leukosis treated with aggressive chemotherapy]. / Remisión completa sin fase de aplasia medular en un paciente con leucosis aguda promielocítica tratado con quimioterapia agresiva.

A patient diagnose of acute promyelocytic leukemia treated with chemotherapy schedule type VAPA. 2 weeks after the administration, there was no response this being the reason to administer a new induction course. 2 weeks after this, a new bone marrow aspiration was performed showing leukemic infiltration with 78% promyelocytes. The clinical situation of the patient did not recommend the addition of more chemotherapy. 10 days later complete remission in bone marrow and blood were demonstrated. The importance of this finding is discussed, complete remission without aplasia, as well as the diagnosis and therapeutic remarks of the case.

[A case of pneumonia by cytomegalovirus in a patient with acute myeloid leukemia]. / Neumonía por citomegalovirus (CMV) en una enferma con leucemia aguda mieloide.

The objective of this clinical case is to suggest that Cytomegalovirus (CMV) should be taken into consideration when dealing with infections produced by opportunistic microorganisms in immunocompromised patients who have fever of unknown origin and especially when accompanied by symptoms and signs of interstitial pneumonia. In the case we report of CMV active infection in a patient with acute myeloid leukemia, the anti-CMV specific treatment (ganciclovir) was iniciated following a positive polymerase chain reaction (PCR) result for CMV. The patient initially experienced an improvement but later worsened and expired. At present there are sensitive and specific techniques such as PCR which make it possible to start specific treatment as soon as the diagnosis of CMV active infection is made.

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control.

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.