José M. Ribera

Influence of Pre- and Post-Transplantation Responses on Outcome of Patients With Multiple Myeloma: Sequential Improvement of Response and Achievement of Complete Response Are Associated With Longer Survival

PURPOSE Complete response (CR) is considered an important goal in most hematologic malignancies. However, in multiple myeloma (MM), there is no consensus regarding whether immunofixation (IF)-negative CR, IF-positive near-CR (nCR), and partial response (PR) are associated with different survivals. We evaluated the prognostic influence on event-free survival (EFS) and overall survival (OS) of these responses pre- and post-transplantation in newly diagnosed patients with MM. PATIENTS AND METHODS We analyzed 632 patients from the prospective Grupo Español de Mieloma 2000 protocol who were uniformly treated with vincristine, carmustine, cyclophosphamide, melphalan, and predisone/vincristine, carmustine, adryamcine, and dexamethasone induction followed by high-dose therapy and autologous stem-cell transplantation. RESULTS Post-transplantation response markedly influenced outcomes. Patients achieving CR had significantly longer EFS (median, 61 v 40 months; P < 10(-5)) and OS (medians not reached; P = .01) versus patients achieving nCR, who likewise had somewhat better outcomes compared with patients achieving PR (median EFS, 34 months, P = .07 v nCR; median OS, 61 months, P = .04). EFS and OS and influence of response were similar among older (age 65 to 70 years) and younger (age < 65 years) patients. Similar findings were observed with pretransplantation response, with trends toward EFS (P = .1; P = .05) and OS (P = .1; P = .07) benefit in patients achieving CR versus nCR and PR, respectively. Post-transplantation response was markedly influenced by pretransplantation response; improvements in response were associated with prolonged survival. CONCLUSION Quality of response post-transplantation, notably CR, is significantly associated with EFS and OS prolongation in newly diagnosed patients with MM. There were trends toward similar associations with pretransplantation response status.

Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome

A risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMA LPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 x 10(9)/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high- risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission after ATRA plus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in the LPA99 (26%; P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Registered at http://www.clinicaltrials.gov as NCT00408278.

Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced- Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival

PURPOSE Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen-identical sibling by using a regimen that uses fludarabine and busulfan. PATIENTS AND METHODS Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m(2)) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil. RESULTS The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS. CONCLUSION Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.

Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy

PURPOSE To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM). PATIENTS AND METHODS We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol. RESULTS Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001). CONCLUSION To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.

Allogeneic Transplant with Reduced Intensity Conditioning Regimens may Overcome the Poor Prognosis of B-Cell Chronic Lymphocytic Leukemia with Unmutated Immunoglobulin Variable Heavy-Chain Gene and Chromosomal Abnormalities (11q− and 17p−)

Purpose: To evaluate the efficacy of reduced intensity conditioning (RIC) allogeneic transplant in 30 patients with poor-prognosis chronic lymphocytic leukemia (CLL) and/or high-risk molecular/cytogenetic characteristics. Experimental Design: Eighty-three percent of patients had active disease at the moment of transplant. That is, 14 of the 23 patients analyzed (60%) had unmutated immunoglobulin variable heavy-chain gene (IgVH) status; 8 of 25 patients (32%) had 11q−, with four of them also displaying unmutated IgVH; and six (24%) had 17p− (five were also unmutated). Results: After a median follow-up of 47.3 months, all 22 patients alive are disease free; overall survival and event-free survival (EFS) at 6 years were 70% and 72%, respectively. According to molecular/cytogenetic characteristics, overall survival and EFS for unmutated CLL and/or with 11q− aberration (n = 13) were 90% and 92%, respectively, not significantly different to those with normal in situ hybridization, 13q− and +12, or mutated CLL (n = 7). All six patients with 17p deletion were transplanted with active disease, including three with refractory disease; all except one reached complete remission after the transplant and two are alive and disease free. Nonrelapse mortality (NRM) was 20%; more than two lines before transplant is an independent prognostic factor for NRM (P = 0,02), EFS (P = 0.02), and overall survival (P = 0.01). Patients older than 55 years have a higher risk of NRM (hazard ratio, 12.8; 95% confidence interval, 1.5-111). Minimal residual disease was monitored by multiparametric flow cytometry in 21 patients. Clearance of CD79/CD5/CD19/CD23 cells in bone marrow was achieved in 68% and 94% of the patients at days 100 and 360, respectively. Conclusion: According to these results, RIC allogeneic transplant could overcome the adverse prognosis of patients with unmutated CLL as well as those with 11q− or 17p−.

Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation.

Autologous stem cell transplantation (ASCT) has been successfully used in HIV-related lymphoma (HIV-Ly) patients on highly active antiretroviral therapy. We report the first comparative analysis between HIV-Ly and a matched cohort of HIV(-) lymphoma patients. This retrospective European Group for Blood and Marrow Transplantation study included 53 patients (66% non-Hodgkin and 34% Hodgkin lymphoma) within each cohort. Both groups were comparable except for the higher proportion of males, mixed-cellularity Hodgkin lymphoma and patients receiving granulocyte colony-stimulating factor before engraftment and a smaller proportion receiving total body irradiation-based conditioning within the HIV-Ly cohort. Incidence of relapse, overall survival, and progression-free survival were similar in both cohorts. A higher nonrelapse mortality within the first year after ASCT was observed in the HIV-Ly group (8% vs 2%), predominantly because of early bacterial infections, although this was not statistically significant and did not influence survival. Thus, within the highly active antiretroviral therapy era, HIV patients should be considered for ASCT according to the same criteria adopted for HIV(-) lymphoma patients.

Autologous Stem-Cell Transplantation in Patients With HIV-Related Lymphoma

PURPOSE Peripheral-blood autologous stem-cell transplantation (ASCT) in patients with HIV-related lymphoma (HIV-Ly) has been reported as a safe and useful procedure. Herein we report the European Group for Blood and Marrow Transplantation experience on patients with HIV-Ly undergoing ASCT. PATIENTS AND METHODS This was a retrospective, multicentric, registry-based analysis. RESULTS Since 1999, 68 patients from 20 institutions (median age, 41 years; range, 29 to 62 years) were included, diagnosed with non-Hodgkins lymphoma (NHL; n = 50) or Hodgkins lymphoma (n = 18). At the time of ASCT, 16 patients were in first complete remission (CR1); 44 patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse (chemo-S); and eight patients had chemotherapy-resistant disease. The median number of CD34(+) cells infused was 4.5 x 10(6)/kg (range, 1.6 to 21.2 x 10(6)/kg). Median time to neutrophil and platelet engraftment were 11 days (range, 8 to 36 days) and 14 days (range, 6 to 455 days), respectively, with a cumulative incidence (CI) at 1 year of 95.6% and 87%, respectively. CI of nonrelapse mortality (NRM) was 7.5% at 12 months after ASCT, mainly because of bacterial infections. CI of relapse was 30.4% at 24 months, statistically related with not being in CR at ASCT (relative risk [RR] = 3.6), NHL histology other than diffuse large B-cell lymphoma (RR = 3.4), and use of more than two previous treatment lines (RR = 3). At a median follow-up of 32 months (range, 2 to 81 months), progression-free survival (PFS) was 56%. Patients not in CR or with refractory disease at ASCT had poorer PFS (RR = 2.4 and 4.8, respectively). CONCLUSION Similarly to HIV-negative patients with lymphoma, ASCT is a useful treatment for patients with HIV-Ly and is associated with low NRM, mainly when performed in early stages and chemo-S disease.

Prolonged survival of patients with angioimmunoblastic T‐cell lymphoma after high‐dose chemotherapy and autologous stem cell transplantation. The GELTAMO experience

Objectives:  Angioimmunoblastic T‐cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high‐dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co‐operative group between 1992 and 2004.

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990–2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%–41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%–50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%–5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome

Flow cytometry (FCM) is more sensitive than conventional cytology for detection of occult leptomeningeal lymphoma; however, some FCM-negative patients show central nervous system (CNS) recurrence. Here, we evaluated the cerebrospinal fluid (CSF) levels of 13 B-cell-associated markers and their contribution to the diagnosis of CNS lymphoma in 91 diffuse large B-cell lymphomas (DLBCL) and 22 Burkitt lymphomas (BLs). From all markers tested, CD19 was the most informative. Thus, higher soluble CD19 (sCD19) levels were associated with a greater frequency of neurological symptoms in DLBCL and BL and with parenchymal CNS lymphoma in DLBCL; sCD19 emerged as a powerful predictor of event-free and overall survival in DLBCL and BL, particularly when combined with FCM detection of CNS disease. These results support the utility of combined FCM detection of lymphoma cells and assessment of sCD19 levels in CSF, for more accurate identification of CNS disease in DLBCL and BL patients.