Michael Kiehl

Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

PURPOSE The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. RESULTS On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. CONCLUSION Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

Evidence of a Graft-Versus-Leukemia Effect in Chronic Lymphocytic Leukemia After Reduced-Intensity Conditioning and Allogeneic Stem-Cell Transplantation: The Cooperative German Transplant Study Group

PURPOSE To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete Remission

PURPOSE The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041). CONCLUSION Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

Summary:We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5–20% blasts (P=0.002) and 14% with >20% blasts (P⩽0.001). Death occurred because of relapse in 29 patients (25.6%), infection in 12 patients (10.6%), acute graft-versus-host disease in eight patients (7.0%) and organ toxicity in nine patients (7.9%). In multivariate analysis, higher number of blasts in the marrow, alternative donors and low Karnofsky performance score were independent adverse prognostic factors for EFS.

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. METHODS Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0-45·5) median progression-free survival was 41·7 months (95% CI 34·9-45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308-2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. INTERPRETATION The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. FUNDING Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.

Treatment of steroid refractory acute and chronic graft‐versus‐host disease with daclizumab

Competitive inhibition of interleukin 2‐dependent lymphocytes by daclizumab demonstrates some beneficial effects in the treatment of graft‐versus‐host disease (GVHD). Sixteen patients with steroid refractory GVHD received daclizumab (1 mg/kg BW) on d 1, 2 (−5), 7, 14 and 21. Twelve patients suffered from grade III–IV acute GVHD and four patients from extensive chronic GVHD. Responses were observed in nine patients (six acute, three chronic GVHD). Fourteen out of 16 patients acquired infections during daclizumab treatment and three deaths were infection related. Daclizumab demonstrates limited activity and is associated with an increased incidence of infectious complications.

Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial

BACKGROUND Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission. METHODS Patients were aged 18-60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m(2) fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00150878. FINDINGS The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% [95% CI 6-21] vs 18% [10-26]; HR 0·62 [95% CI 0·30-1·31]). Relapse incidence (cumulative incidence 3 years 28% [95% CI 19-38] vs 26% [17-36]; HR 1·10 [95% CI 0·63-1·90]), disease-free survival (3 year disease-free survival 58% [95% CI 49-70] vs 56% [46-67]; HR 0·85 [95% CI 0·55-1·32]), and overall survival (3 year overall survival 61% [95% CI 50-74] vs 58% [47-70]; HR 0·77 [95% CI 0·48-1·25]) did not differ significantly between groups. Grade 3-4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups. INTERPRETATION Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission.

Management of sepsis in neutropenia: guidelines of the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

These guidelines from the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO) give recommendations for the management of adults with neutropenia and the diagnosis of sepsis. The guidelines are written for clinicians and focus on pathophysiology, diagnosis, and treatment of sepsis. The manuscript contains evidence-based recommendations for the assessment of the quality and strength of the data.

Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients: Guidelines of the infectious diseases working party of the German Society of Haematology and Oncology☆

Patients with neutropenia lasting for more than 10d, who develop fever and pulmonary infiltrates, are at risk of treatment failure under conventional broad-spectrum antibacterial therapy. Filamentous fungi are predominant causes of failure, however, multi-resistant gram-negative rods such as Pseudomonas aeruginosa or Stenotrophomonas maltophilia may be involved. Prompt addition of mould-active systemic antifungal therapy, facilitated by early thoracic computed tomography, improves clinical outcome. Non-culture-based diagnostic procedures to detect circulating antigens such as galactomannan or 1,3-beta-d-glucan, or PCR techniques to amplify circulating fungal DNA from blood, bronchoalveolar lavage or tissue specimens, may facilitate the diagnosis of invasive pulmonary aspergillosis. CT-guided bronchoalveolar lavage is useful in order to identify causative microorganisms such as multidrug-resistant bacteria, filamentous fungi or Pneumocystis jiroveci. For pre-emptive antifungal treatment, voriconazole or liposomal amphotericin B is preferred. In patients given broad-spectrum azoles for antifungal prophylaxis, non-azole antifungals or antifungal combinations might become first choice in this setting. Antifungal treatment should be continued for at least 14 d before non-response and treatment modification are considered. Microbial isolates from blood cultures, bronchoalveolar lavage or respiratory secretions must be critically interpreted with respect to their aetiological relevance for pulmonary infiltrates.

Infectious complications after allogeneic stem cell transplantation: epidemiology and interventional therapy strategies Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows transplantation.