First-line treatment with R-CHOP or rituximab-bendamustine in patients with follicular lymphoma grade 3A-results of a retrospective analysis.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed.

Consensus statement for cancer patients requiring intensive care support.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL).

BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18.

[Bone marrow carcinosis as initial presentation of adenocarcinoma]. / Infiltration des Knochenmarks und disseminierte intravasale Gerinnung. Seltene Erstsymptome eines soliden Tumors.

Bone marrow infiltration by a solid tumor is an uncommon event. We report about a female patient presenting with shortness of breath und abnormalities of blood counts. A bone marrow aspiration showed the infiltration due to adeno carcinoma. The detection of the primary was not successful. Our patient died within 6 days due to disseminated intravascular coagulation.

Allogeneic hematopoietic stem cell transplantation for patients with relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

Information regarding the curative role of allogeneic stem cell transplantation (allo-HCT) in systemic anaplastic large cell lymphoma (sALCL) is scarce. We analyzed the results of allo-HCT in patients with relapsed/refractory sALCL with special emphasis on the role of brentuximab vedotin (BV) as a bridge to allo-HCT. Forty-four patients (24 females, median age 38 years) with sALCL were included. Twenty-three patients (52%) received BV before allo-HCT; BV-treated patients were more heavily pretreated (≥3 lines of therapy in 74% vs. 38%, p = 0.04). Twenty-three patients (52%) were in complete remission (CR) at allo-HCT. Three-year nonrelapse mortality and incidence of relapse (IR) after allo-HCT were 7% and 40%, respectively. With a median follow-up of 39 (12-69) months for survivors, 3-year progression-free survival (PFS) and overall survival were 53% and 74%, respectively. Univariate analysis showed that heavily pretreated patients and those not in CR had a higher IR and a lower PFS. The use of BV before transplant did not impact on any of the outcomes. Allo-HCT is a curative therapeutic strategy in a significant proportion of patients with relapsed/refractory sALCL; BV does not seem to modify transplant-related outcomes but might be able to render more patients candidates for this curative treatment.

[Prevalence of cancer patients in German intensive care units]. / Prävalenz von Krebspatienten auf deutschen Intensivstationen.

INTRODUCTION: Cancer is one of the leading causes of death worldwide. Due to increasing comorbidities, age and aggressive chemotherapy, care of cancer patients in intensive care units (ICUs) is more and more necessary. So far, little is known about the care structure of cancer patients in German ICUs. The aim of this work is to collect and evaluate the prevalence and care data of cancer patients on two reference dates. METHODS: German ICUs were invited to participate in a 2-day, prospective, multicenter point prevalence study in ICU cancer patients. Participation in the study was voluntary and the study was not funded. An ethics vote was obtained to conduct the study. The data were anonymously entered into an eCRF (electronic case report form) by the participating centers. Identification of the patients is therefore not possible. RESULTS: About one in four patients on the ICU/IMC ward had hematological-oncological (HO) disease (n = 316/1319, 24%). The proportion depended significantly on the number of beds in each hospital. The most frequent reasons for admission to the ICU/IMC station were postoperative monitoring (n = 83/221, 37.6%), respiratory instability (n = 79/221, 35.7%), circulatory instability (n = 52/221; 23.5%) and the severe infection with sepsis (n = 47/221; 21.3%). In all, 66.5% (n = 147/221) of the patients had a solid tumor and 21.7% (n = 48/221) had hematological cancer, 78.3% (n = 173/221) of the documented cancer patients received "full-code" intensive management, while 42.5% (n = 94/221) of the HO patients were ventilated and 40.7% (n = 90/221) required catecholamines. The median (mean; IQR) SAPS II score was 35 (37.79, IQR = 24-48) and the median (mean, IQR) TISS score was 10 (13.26, IQR = 10-15). Through the analysis and evaluation of the data available in the context of the prevalence study, it was possible for the first time to determine the Germany-wide cross-center prevalence and care situation of hematological cancer patients in intensive care and intermediate care stations. About one in four patients on German ICUs and IMC wards have a major or minor cancer diagnosis (n = 316/1319 = 24%). Care management is complex in this patient population and requires close interdisciplinary collaboration.

Net reclassification improvement with serial biomarkers and bed-sided spirometry to early predict the need of organ support during the early post-transplantation in-hospital stay in allogeneic HCT recipients.

To predict the need of intensive care unit admission with organ support during the transplantation hospital stay in 101 consecutives allogeneic hematopoietic cell transplantation (allo-HCT) recipients the added predictive utility of three times per week Copeptin, MR-proADM, MR-proANP, NT-proBNP, IL-6, Procalcitonin, D-dimer and three times per week bed-sided pulmonary function test was determined in comparison with an index model. The index model was calculated by multivariate regression analysis out of the patients' routine laboratory parameters. To calculate the added predictive utility of the investigated markers the Δ-AUC and the continuous net reclassification improvement (cNRI + 2 to - 2), splitted for events and non-events were calculated for each marker in comparison with the index model. According to the Δ-AUC, none of the parameters improved risk prediction. In contrast, the cNRI was significantly improved for events and non-events by Copeptin (event 0.75, p value 0.0013; non-event 0.4, p value 0.000079) and for events by NT-proBNP (0.6, p value 0.018). D-dimer and PCT significantly predicted the non-event. Of the spirometry parameters, the FEF50% improved prediction of event and non-event according to the cNRI model. Our data support the additional serial analysis of Copeptin and NT-proBNP in allo-HCT recipients during the transplantation hospital stay.

Pelvic magnetic resonance imaging after bone marrow harvest--a retrospective study in 50 unrelated marrow donors.

A total of 50 unrelated marrow donors were examined by pelvic magnetic resonance imaging (MRI) to investigate the morphological sequelae of bone marrow harvesting (BMH). Signal increase in T2-weighted sequences and contrast media enhancement in T1 sequences at the operative sites were found as typical MRI morphology 4 weeks after harvest (group A, n=16), corresponding to edema, hyperemia and proliferative activity. Although tissue repair was completed in the majority of donors 1 year after BMH, about 36% of donors in group B (n=16) had abnormal findings. These included a persistence of the 'acute injury' signal pattern (2/16, 12%), and signal alterations due to fatty marrow conversion (4/16, 24%). The proportion of MRI abnormalities increased to over 70% in two-time donors (group C, n=11), which might indicate a cumulation of tissue damage after repetitive harvests. If donors had experienced prolonged discomfort after BMH (group D, n=7), MRI revealed pathological signals in 86%. In conclusion, the MRI morphology reflects the pathophysiological reactions after BMH, including inflammation and tissue repair. A further prospective evaluation in a larger number of donors is necessary to confirm these results and to identify the factors which influence the extent and duration of tissue damage.

Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers.

Sequential analysis of chimerism after allogeneic blood stem cell transplantation (BSCT) has been shown to be predictive for graft failure and relapse. We have explored the impact of a novel approach for the quantitative determination of chimerism using a commercial PCR assay with multiplex amplification of nine STR-loci and fluorescence detection. The feasibility was studied in 121 patients transplanted from related or unrelated donors. Follow-up investigation was performed in 88 patients. Twenty-eight of these patients had received a transplantation after dose-reduced conditioning therapy. Results were compared to data obtained by FISH analysis in a subgroup of patients receiving grafts from sex-mismatched donors. The analysis was possible in all patients, the median number of informative alleles was 4 (range 1-8) compared to 7 (range 1-9) in the related and unrelated situation, respectively. A good correlation was seen in 84 samples from 14 patients analyzed in parallel with STR-PCR and FISH. Decreasing values of donor chimerism were detected prior to or concomitantly with the occurrence of graft failure and relapse of disease in all patients investigated prospectively. Using FACS-sorted material, eg peripheral blood CD34+ cells, the assay permitted the detection of residual recipient cells with high sensitivity (down to one CD34+ Kasumi cell in 40,000 normal WBC). Evaluation of the inter-laboratory reproducibility revealed that in 20 samples analyzed in three different centers, the median coefficient of variation was 2.1% (range 0.7-9.6%). Taken together, the results support the use of the test as a valuable tool in the follow-up of patients undergoing allogeneic BSCT. In cases lacking PCR-detectable disease-specific gene products, this assay may represent an alternative to recently established real-time PCR methods.

CD34+ cell dose, conditioning regimen and prior chemotherapy: factors with significant impact on the early kinetics of donor chimerism after allogeneic hematopoietic cell transplantation.

The aim of this study was to define factors that significantly influence the early kinetics of donor chimerism after transplantation. In a retrospective study, the percentage of donor chimerism in peripheral blood measured with sex-chromosome-specific probes and fluorescence-in situ hybridization was analyzed in 184 recipients of allogeneic hematopoietic cells between days 1 and 30. Using a generalized linear model for longitudinal observations, the dose of CD34+ cells infused had a significant impact on the slope of donor chimerism. In multivariate analysis, cell doses of 2-8 x 10(6)/kg (P=0.001) and <2 x 10(6) CD34+ cells/kg (P<0.0001) were associated with slower increase of donor chimerism compared to >8.0 x 10(6) CD34+ cells/kg. In addition, fludarabine-based reduced-intensity conditioning resulted in a significant delay of donor cell increase compared to standard conditioning therapy (P=0.0001). The application of chemotherapy before the start of conditioning (P=0.0003) and the use of antithymocyte globulin (P=0.003) were associated with a faster increase of donor chimerism. The factors identified in this study can be used to predict the kinetics of early donor chimerism for an individual patient.

Faster engraftment of peripheral blood progenitor cells compared to bone marrow from unrelated donors.

Twenty-six patients received peripheral blood progenitor cells (PBPC) from unrelated donors at five European Centres. Twenty-five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-5 days. Eleven patients receiving PBPC were compared to 11 patients receiving unrelated bone marrow with comparable prognostic factors. The median mononuclear cell count, the CD3+ cells and the CD56+ cells were seven to 10 times higher in PBPC, compared to bone marrow (P < 0.001). The median CD34+ cell content was 6.1 x 10(6)/kg recipient weight with PBPC, compared to 4.3 with bone marrow (NS). Time from transplantation to neutrophils >0.5 x 10(9)/l was a median of 11 (range 6-21) days using PBPC vs 15 (10-22) days after transplantation of bone marrow (P = 0.03). Transfusions and time to discharge did not differ between the two groups. All 26 patients receiving PBPC engrafted. Acute GVHD grades II-IV was seen in 8/26 (31%) and chronic GVHD in 8/18 (44%). Overall, 13/26 (50%) of the patients are alive and well with a median follow-up of 9 (2-35) months.

Flow cytometric DNA quantification in immunophenotyped cells as a sensitive method for determination of aneuploid multiple myeloma cells in peripheral blood stem cell harvests and bone marrow after therapy.

The simultaneous measurement of DNA content and myeloma-related antigens (B-B4 or CD38) by flow cytometry is proposed as a method for the detection of aneuploid plasma cells in peripheral blood stem cell (PBSC) harvests and in bone marrow after therapy. In 30 patients with initially detected aneuploid myeloma cells we evaluated the bone marrow after therapy and in eight of these patients 23 PBSC harvests were analyzed. In 13 of 23 PBSC harvests aneuploid myeloma cells were detectable (range: 0.02-0.63%). In the bone marrow of the 30 patients aneuploid plasma cells were detectable in all samples after chemotherapy (range: 0.12-35.70%) and after autologous PBSC transplantation in two of three patients (0.21% and 0.03%). Furthermore the relationship between diploid and aneuploid plasma cells can be evaluated. In the PBSC harvests the percentage of aneuploid plasma cells is significantly lower than that of diploid plasma cells (P=0.006). In contrast, in bone marrow the aneuploid plasma cells are predominant in most patients even after therapy (24 of 30 patients; P=0.0055). In the case of initially detected aneuploid myeloma cells, a contamination with malignant cells can be estimated with a simple flow cytometric method in PBSC harvests and in bone marrow after therapy.

Acceptance and feasibility of peripheral stem cell mobilisation compared to bone marrow collection from healthy unrelated donors.

Allogeneic peripheral blood stem cell transplantation leads to an earlier engraftment compared to BMT. The feasibility, acceptance and long-term side-effects of G-CSF mobilisation of PBSC in unrelated healthy donors needs to be evaluated. Forty unrelated healthy donors received G-CSF in a dose of 10 microg/kg bodyweight for 5 days and two aphereses were performed. The donors were monitored prospectively. The data were compared to bone marrow harvests from unrelated donors. Almost all stem cell donors reported some side-effects due to Filgrastim application. Bone pain (32), headache (20), chest pain (two) and night sweats (one) were complained of. By taking analgesics, the pain was relieved in most cases. No donor discontinued the filgrastim application. Bone pain and headache resolved within 2-4 days after termination of Filgrastim application. There was, as expected, a seven-fold increase in the number of total WBCs. There were no significant changes of platelet counts during G-CSF application. After 4 weeks haemoglobin concentration and platelet counts showed no significant differences compared to baseline values. The aphereses were mostly tolerated very well. Eighteen donors reported paraesthesia, one donor developed dizziness, two complained of nausea and vomiting. There was a significant decrease in platelet count (242 before, 98 x 10(9)/l after aphereses). Autologous platelets were transfused after the second aphereses in four donors. These data were compared to data from 245 unrelated bone marrow donors, who had on average, 14 days bone pain and tiredness after donation. The G-CSF mobilisation and apheresis of peripheral blood stem cells is an alternative to traditional bone marrow harvesting in unrelated healthy donors. It is well tolerated and the duration of side-effects on average is shorter than after the surgical procedure. So far no long-term effects have been observed in the follow-up.

Dose-reduced conditioning for allogeneic blood stem cell transplantation: durable engraftment without antithymocyte globulin.

Between February 1998 and October 1999, 24 patients with advanced leukemia, lymphoma or solid tumors received G-CSF mobilized peripheral blood stem cells (PBSC) from HLA-matched sibling donors after dose-reduced conditioning therapy. Only patients with reduced performance status or major infectious complications, not eligible for standard transplant procedures, were included. The 5-day conditioning therapy consisted of 3.3 mg/kg intravenous busulphan x 2 days and 30 mg/m2 fludarabine x 5 days. GVHD prophylaxis was performed with either CsA alone (n = 5), CsA combined with short course methotrexate (n = 5) or mycophenolate mofetil (n = 14). The day 100 survival was 95.2% for the whole group. All patients engrafted after a median of 15 days (range, 11-19) and 12.5 days (range, 10-19) for neutrophils and platelets, respectively. The median time to a neutrophil count of <0.5 x 109/l was 7 days (range, 2 to 12). Acute GVHD >I was observed in six patients, whereas eight patients have signs of chronic GVHD. The prospective 12 month overall survival with a median follow-up of 7 months is 63%. Relapse of disease and toxicity associated with chronic GVHD were the main causes of death. The treatment-related mortality was 12.5%. Dose-reduced conditioning using intravenous busulphan and fludarabine allows stable engraftment without ATG in related transplants and leads to a reduction of transplant-related mortality.

Evidence for a graft-versus-tumor effect in refractory ovarian cancer.

PURPOSE: A 31-year-old woman suffered a 4th relapse of epithelial ovarian cancer refractory to several cytotoxic drugs including platinum, paclitaxel, and topotecan. METHODS: Sequential high-dose chemotherapy with autografting (three courses) led to a minor response of short duration. In order to induce a graft-versus-tumor effect, allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical sibling donor, after dose-reduced conditioning, was performed in January 2001. RESULTS: On day +51 the patient developed acute grade II graft-versus-host disease of the skin and gastrointestinal tract, which was successfully treated by prednisolone. Six months after allogeneic HSCT a complete disappearance of the tumor could be seen. Unfortunately, 14 months later a 5th relapse was diagnosed. CONCLUSIONS: This case demonstrates, on the one hand, that allogeneic HSCT is able to induce complete remissions (CR) in chemoresistant ovarian cancer. On the other hand, despite achievement of CR after allografting, the chance of cure remains limited for these patients.

Salvage chemotherapy with mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in relapsing and refractory lymphoma.

PURPOSE: The aim of the study was to evaluate the feasibility and efficacy of the combination of mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in patients with prognostically unfavorable recurrent and refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). METHODS: Forty-six patients (median age 43 years, range 18-63) with relapsed (n = 15) or refractory (n = 31) malignant lymphoma were enrolled (HD, n = 13; low-grade/transformed NHL, n = 4; high-grade NHL, n = 29). A total of 39 patients (85%) showed multiply relapsed diseases with a duration of prior remission of < 12 months (n = 8) or had lymphoma being resistant to prior chemotherapy (n = 31). The MIFAP therapy consisted of fludarabine (15 mg/m2, q. 12 h, day 1-4), cytarabine (50 mg/m2 by continuous infusion (CI) over 22 h, day 1-4), cisplatin (25 or 30 mg/m2 by CI over 24 h, day 1-4), and mitoxantrone (4 mg/m2, day 2-5). RESULTS: Thirteen patients (28%) achieved complete remission (CR) and 15 patients (33%) partial remission (PR), for an overall response (OR) rate of 61%. Twenty-two patients responding to MIFAP (10 CR, 12 PR) have been consolidated by high-dose therapy (HDT) with hematopoietic stem cell transplantation (SCT). After a median follow-up of 12 months, 16 patients are in continuous CR (CCR) (n = 14) or CCRu (unconfirmed) (n = 2). The median duration of event-free survival (EFS) and overall survival (OS) were 6.5 and 19.3 months, respectively. Probabilities of EFS and OS after 3 years were 19% and 40%. Responders consolidated by subsequent HDT showed rates for 3-year EFS and OS of 40% and 66%, respectively. Unfavorable prognostic factors for EFS by univariate analysis were refractory lymphoma and the presence of B-symptoms. Significant prognostic factors for OS were NHL, refractory lymphoma, B-symptoms, and bone marrow involvement. The major toxicities were leukocytopenia and thrombocytopenia of the World Health Organization (WHO) grade IV in nearly all courses (median duration 10 and 11 days). In contrast, non-hematological side effects were moderate, predominantly of WHO grades I and II. Treatment-related mortality with MIFAP was 4% (two patients with septicemia by Aspergillus fumigatus). CONCLUSIONS: MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases.

Complex cytogenetic and immunophenotypic aberrations in a patient with Sezary syndrome.

Sezary syndrome is defined as the leukemic variation of cutaneous T-cell lymphomas. Here we describe the cytogenetic pattern of peripheral T-cells of a 50-year-old male patient suffering from this disease. We used Giemsa-banding (G-banding) technique and a fluorescence in situ hybridization (FISH) assay to determine cytogenetic changes affecting 15 different chromosomes. The cells displayed an abnormal hypodiploid karyotype with a prominent insertion located at the short arm of chromosome 1. Unbalanced translocations were observed involving chromosomes 4 and 14. Besides other abnormalities we detected a 6q- deletion. These multiple genetic changes may reflect the high aggressivity of the neoplastically transformed T-cell population and the poor response to chemotherapeutic treatment.