Guillermo Martin

Absence of platelet response after eradication of Helicobacter pylori infection in patients with chronic idiopathic thrombocytopenic purpura

Eradication of Helicobacter pylori infection has been associated with the correction of thrombocytopenia in patients with idiopathic thrombocytopenic purpura (ITP). We have analysed the response to eradication of H. pylori in a series of 56 adult patients with chronic ITP. Forty patients had H. pylori infection (71%) that was eradicated in 23 of 32 evaluable patients (72%). Platelet counts did not significantly vary according to H. pylori treatment outcome. Three of 56 patients (5%) achieved a partial response attributable to H. pylori eradication. Therefore, detection of H. pylori infection should not be routinely included in the initial work‐up of ITP.

Extramedullary relapse in acute promyelocytic leukemia treated with all- trans retinoic acid and chemotherapy

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26 950/mm3 (7700–162 000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARα isoform (P=0.0003) and high WBC counts (⩾10 000/mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P=0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (⩾10 000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC ⩾10 000/mm3 at diagnosis remains to be established.

Acute promyelocytic leukemia. Therapy results and prognostic factors.

From December 1976 to July 1986, 34 patients with acute promyelocytic leukemia (APL) were treated with daunorubicin (DNR) alone and simultaneous supportive therapy with low‐dose heparin, platelet transfusions, and fresh frozen plasma. Two consecutive maintenance therapy regimens were employed in patients who achieved complete remission (CR): (1) a classical maintenance with methotrexate and 6‐mercaptopurine, with DNR plus methyl‐GAG reinductions; (2) from 1982 an intensive sequential combination therapy regimen was administered. CR was achieved in 23 patients (68%). Only one patient had leukemic resistance. Other failures were a consequence of postchemotherapy complications. A multivariate logistic regression analysis has been performed to evaluate the prognostic importance on response to remission induction of 25 patient and disease characteristics at diagnosis. The significant variables in decreasing order of significance were: serum albumin level, fever at diagnosis, serum creatinine level, and age. The median duration of remission and survival by Kaplan‐Meier analysis were projected to be 24 and 25 months, respectively. Relapses occurred in 11 of 23 CR patients. Nine patients remained in the first remission from 5+ to 37+ months. Short‐term (CR) and long‐term results (duration of remission and survival) in APL treated for induction with DNR alone were similar to those obtained in other subtypes of acute myeloblastic leukemia by intensive combination chemotherapy.

Treatment With All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group

PURPOSE To analyze the simultaneous combination of all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for children with acute promyelocytic leukemia (APL). PATIENTS AND METHODS Since November 1996, 66 children (younger than 18 years) with genetically proven APL received induction therapy with ATRA and idarubicin. Consolidation therapy consisted of three courses of anthracycline monochemotherapy. After November 1999, patients with intermediate and high risk of relapse received consolidation therapy with ATRA and slightly reinforced doses of idarubicin. Maintenance therapy consisted of ATRA and low-dose mercaptopurine and methotrexate. RESULTS Thirty-nine girls (59%) and 27 boys (41%) were included in this study. The WBC count at presentation was more than 10 x 10(9)/L in 26 patients (39%). Sixty-one children (92%) achieved complete remission (CR). Early deaths from hemorrhage and retinoic acid syndrome occurred in three patients and two patients, respectively. Toxicity was manageable during consolidation and maintenance therapy. No deaths in CR, clinical cardiomyotoxicity, or secondary malignancy occurred. Two patients had molecular persistence at the end of consolidation. Three clinical relapses and two molecular relapses were also observed. Apart from one molecular relapse, all these events occurred among children with hyperleukocytosis. The 5-year cumulative incidence of relapse was 17%, whereas disease-free and overall survival rates were 82% and 87%, respectively. CONCLUSION A high incidence of hyperleukocytosis in children with APL was confirmed. Besides low toxicity and a high degree of compliance, a risk-adapted therapy combining ATRA and anthracycline monochemotherapy showed an antileukemic efficacy comparable to those previously reported with other chemotherapy combinations in children.

Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model

Tumor lysis syndrome may represent a life-threatening complication during induction chemotherapy of acute myeloid leukemia. This study shows that pretreatment elevated serum lactate dehydrogenase, increased serum creatinine, high uric acid, and markedly elevated white blood cell counts represent independent risk factors for this complication. See related perspective on page 9. Background Despite the prophylactic use of allopurinol, tumor lysis syndrome (TLS)-related morbidity and mortality still occur in a number of patients with acute myeloid leukemia (AML). The aim of this study was: (i) to analyze the incidence and outcome of TLS in a large series of patients with AML receiving hyperhydration and allopurinol, (ii) to identify risk factors for TLS, and (iii) to develop a prognostic scoring system for estimating individual risk of TLS. Design and Methods The study included 772 adult patients with AML receiving induction chemotherapy between 1980 and 2002. TLS was divided into laboratory TLS (LTLS) or clinical TLS (CTLS). The population study was randomly divided into training and test subsets, so that a prognostic model for CTLS was developed in one set and validated in the other. Results Overall, 130 patients (17%) developed TLS (5% CTLS and 12% LTLS). Unlike LTLS, CTLS was associated with a higher rate of death from induction therapy. Multivariate analysis showed that pretreatment serum lactate dehydrogenase (LDH) levels above laboratory normal values, creatinine >1.4 mg/dL, uric acid >7.5 mg/dL and white blood cell (WBC) counts >25 × 109/L were independent risk factors for CTLS and LTLS. The scoring system, based on pretreatment WBC counts, and uric acid and LDH serum levels, had excellent discrimination and was accurate for predicting CTLS and LTLS. Conclusions TLS is frequently observed in AML patients during induction therapy. Only the development of CTLS had an impact on higher mortality rate from induction therapy. The scoring system derived from this study can be used to obtain an accurate estimate of the individual risk of TLS, allowing for risk-adapted prophylaxis against this complication.

Early infections in adult patients undergoing unrelated donor cord blood transplantation

Early transplant-related mortality after cord blood transplantation from unrelated donors (UD-CBT) is close to 50%, mainly due to infectious complications. We have studied the incidence and characteristics of early infections (before day 100) in a series of 27 adult patients (median age 30 years, range 16–46) undergoing UD-CBT at a single institution. All 27 patients experienced at least one infectious episode and 18 (66%) suffered a severe infection. Bacteremia occurred in 55% of patients (13 with Gram-positive and 11 with Gram-negative microorganisms). Eleven of 19 CMV-seropositive patients (58%) developed CMV antigenemia and one patient had CMV disease. Fungal infections were documented in three patients (11%), comprising invasive fungal infections in two cases and a localized esophagitis in one. Ten patients (37%) died before day 100 after transplantation. Infection was considered the primary cause of death in four patients (sepsis by Acinetobacter spp. bacteremia in three cases) and contributed to death in another four. The most striking findings in this series were the high incidence of, and mortality due to multiresistant Acinetobacter spp. and the low incidence of and lack of mortality due to CMV disease. This report confirms that infection is a major complication in adults undergoing UD-CBT.

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⩽40 and male gender were favorable variables for survival, whereas molecular response predicted longer leukemia-free survival. In conclusion, early institution of salvage therapy at molecular failure, before onset of hematological relapse, is beneficial in APL. Moreover, given the poor outcome of HEMrel managed with ATRA and HDAC, use of alternative therapeutic strategies in this setting is warranted.

Cord Blood Transplantation from Unrelated Donors in Adults with High-Risk Acute Myeloid Leukemia

Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelated donors are limited. We analyzed the outcome and prognostic factors of 49 adults with high-risk acute myelogenous leukemia (AML) receiving single-unit CBT from unrelated donors after myeloablative (MA) conditioning at a single institution. Conditioning regimens were based on the combination of thiotepa, busulfan (Bu), cyclophospamide (Cy), or fludarabine (Flu), and antithymocyte globulin (ATG). Cumulative incidence of myeloid and platelet engraftment was 96% and 73% at a median time of 20 and 62 days, respectively. Engraftment was significantly faster for patients receiving higher doses of CD34(+) cells. Confidence Interval of graft-versus-host disease (GVHD), acute GVHD (aGVHD) grade II-IV, III-IV, and extensive chronic GVHD (cGVHD) were 26%, 15%, and 30%, respectively. Leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse at 2 years were 42%, 39%, and 19%, respectively. Low number of total nucleated cells (TNC) had a negative impact on NRM and LFS. Patients transplanted in first complete remission (CR1) receiving TNC above 2 x 10(7)/kg had a 4-year LFS of 75%. These results show that CBT from unrelated donors is a curative treatment for a substantial number of patients with high-risk AML, particularly if transplant is performed with highly cellular units in patients in first CR.

Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission : a report from a single institution

PURPOSE To determine if peripheral-blood stem cells (PBSC) collected during the recovery of standard induction and consolidation chemotherapy in acute myeloblastic leukemia (AML) can be used as a safe tool for autologous transplantation, and to study aspects of the autologous blood stem-cell transplantation (ABSCT) procedure and their results in AML patients in first remission. PATIENTS AND METHODS Twenty-four AML patients in first remission received busulfan (BU; 16 mg/kg) and cyclophosphamide (CY; 200 mg/kg) followed by ABSCT. PBSC were collected by continuous-flow leukaphereses after induction and consolidation courses. RESULTS The median numbers of mononuclear cells (MNCs) and colony-forming unit granulocyte-macrophage (CFU-GM) administered were 6 x 10(8)/kg and 11 x 10(4)/kg, respectively. ABSCT induced engraftment in 22 patients and there were two graft failures. The median times to reach a polymorphonuclear (PMN) leukocyte count of 0.5 x 10(9)/L and a platelet count of 50 x 10(9)/L were 13 and 19 days, respectively. Fatal hepatic veno-occlusive disease (VOD) was observed in two cases. Other toxicities were mild and uncommon. Twelve patients relapsed between 1 and 9 months posttreatment. Actuarial disease-free survival (DFS) and actuarial risk of relapse at 30 months were 35% (95% confidence interval [CI], 25% to 45%) and 60% (95% CI, 50% to 72%), respectively. CONCLUSION These preliminary results show the fast hematopoietic recovery and the low infectious and hemorrhagic morbidity associated with the procedure and strongly suggest that ABSCT may be as effective as autologous bone marrow transplantation (ABMT) in AML. However, further strategies for reducing leukemic relapse must still be investigated.

Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation

CBV and BEAM are the two most frequently used regimens for patients with lymphoma undergoing autologous hematopoietic stem-cell transplantation (ASCT). This study compared their morbidity and transplant-related mortality (TRM) in 113 patients with non-Hodgkins lymphoma (69) and Hodgkins disease (44) undergoing ASCT between 1990 – 2004. CBV (cyclophosphamide, 6000 mg m−2; VP-16, 750 mg m−2; and high-dose BCNU, 800 mg m−2) was administered to 75 patients and 38 received BEAM (BCNU, 300 mg m−2; VP-16, 800 mg m−2; cytarabine, 800 mg m−2; melphalan, 140 mg m−2). Patients in the BEAM group had a significantly higher median age (p = 0.002) and were more heavily treated before ASCT (p = 0.003). More patients showed active disease at transplant in the BEAM group (p = 0.04). Sinusoidal obstruction syndrome (SOS) was more frequent in the CBV group (11% vs 0%, p = 0.048). There were 20 (18%) transplant-related deaths, 18 in the CBV and two in the BEAM group. Infectious complications (12 patients, seven with pneumonia) and SOS (four) were the most frequent causes of death. The cumulative incidences of TRM were 25% in the CBV and 7% in the BEAM group (p = 0.02). CBV thus produced a higher incidence of SOS and TRM than BEAM in this series.