Elchanan H. Januszewicz

Inhibition by Retinoic Acid of Myeloid Progenitors in Chronic Myeloid Leukemia and Myeloproliferative Disease: Increased Sensitivity in Blastic Phase of Chronic Myeloid Leukemia

&NA; The effects of all‐trans retinoic acid (RA) were tested on the growth in vitro of myeloid progenitors from peripheral blood or bone marrow, in 25 patients with chronic myeloid leukemia (CML), ten of whom were either in accelerated or blastic phase, and in nine patients with myeloproliferative disease (MPD). The responses were compared with 12 normal bone marrow controls obtained from patients with lymphoma. Clonal growth in CML blastic and accelerated phase was inhibited to the greatest degree (mean 49±9% (SEM) of control at 0.3 µM RA). The responses in CML chronic phase and MPD were more heterogeneous, but significant inhibition was seen at higher concentrations of RA (50 ± 12% CML chronic phase, 58 ± 26% MPD at 3.0 µM RA). At 0.3 µM and 1.0 µM RA there were significant differences between the CML chronic phase and the CML blastic phase patients (p < 0.02 and p < 0.05 respectively). At these concentrations there was no significant inhibition on normal bone marrow myeloid progonitors. Inhibition was independent of the proportions of progenitors in S phase, as assessed by tritiated thymidine suicide. Preincubation of cells from selected patients with RA for 48 hours before culture in agar resulted in a significant degree of inhibition (48 ± 8% of control). Inhibition was prevented by delaying the addition of RA from 24 to 48 hours from the beginning of the culture, indicating that RA exerts an early direct effect on myeloid progenitors.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy

Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6–125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0–7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P=0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P=0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.

Predictive factors for successful stem cell mobilization in patients with indolent lymphoproliferative disorders previously treated with fludarabine.

Predictive factors for successful stem cell mobilization in patients with indolent lymphoproliferative disorders previously treated with fludarabine

A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma

Background:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.Methods:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP ‘group 1’; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX ‘group 2’; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX ‘group 3’.Results:Overall, 217 patients were identified (49, 125 and 43 in groups 1–3, respectively). With median follow-up of 3.4 (range 0.2–18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1–3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5–33.1%), 6.9% (3.5–13.4%) and 2.3% (0.4–15.4%) in groups 1–3, respectively (P=0.009).Conclusions:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Prognostic impact of monocyte count at presentation in mantle cell lymphoma

An increased number of circulating monocytes at presentation has recently been associated with shorter survival in Hodgkin lymphoma, follicular lymphoma and diffuse large B cell lymphoma. This study aimed to assess the prognostic impact of the absolute monocyte count (AMC) at diagnosis in mantle cell lymphoma (MCL). AMC at diagnosis was available in 97 MCL cases recorded in the databases of the Oncology Institute of Southern Switzerland in Bellinzona (Switzerland) and the Division of Haematology of the Amedeo Avogadro University of Eastern Piedmont in Novara (Italy). With a median follow up of 7 years, the 5‐year overall survival was 29% for patients with AMC >0·50 × 109/l and 62% for patients with AMC ≤0·50 × 109/l (P = 0·008). Elevated AMC and beta‐2 microglobulin at diagnosis remained independent outcome predictors at multivariate analysis, controlling for the MCL International Prognostic Index (MIPI), and have been used to build a simple prognostic scoring system. In this relatively small and heterogeneous series an increased AMC identified poor‐risk patients. Our results suggest that AMC together with the beta‐2 microglobulin level might provide an inexpensive way to stratify MCL patient risk as a complement to the MIPI, which was confirmed to be a very powerful prognostic tool.

Docetaxel effectively mobilizes peripheral blood CD34 + cells

We prospectively evaluated docetaxel (100 mg/m2) with g-csf (10 μg/kg s.c., daily) for mobilization efficiency in 26 patients with breast cancer. the minimum target yield was >4.5 × 106 CD34+ cells/kg (optimum = 9 × 106/kg), sufficient to support the subsequent three cycles of high-dose therapy (HDT). The peak days for peripheral blood (PB) CD34+ cells were day 8 and day 9. Seven collections began on day 7, 16 on day 8 and three on day 9. The median peripheral blood progenitor cell (PBPC) CD34+ cell content ranged from 1.2 to 5.9 × 106/kg per day during days 7 to 11 with a median CD34+ content of the total 72 PBPC collections of 3.4 × 106/kg (0.07–15.6). Fifteen patients obtained a PBPC collection exceeding 5 × 106/kg on a single day of collection. Following a median 3 days collection for each patient (range 2–4), the median total CD34+ for all individual sets of collections was 9.7 × 106/kg (range 1.0–28.4). We were able to achieve the minimum CD34+ cell target yield in 22 of 26 patients with one cycle of mobilisation chemotherapy and in two of these patients a second collection yielded sufficient cells. twenty-two patients have subsequently received repetitive hdt and pbpc transplantation with 57 cycles of hdt having been delivered. for all 57 cycles, the median time to absolute neutrophil count (anc) >0.5 × 109/l and 1.0 × 109/l was 10 days (range 8–22) and 11 days (range 8–23), respectively. The median time to platelets greater than 20 × 109/l, 50 × 109/l and 100 × 109/l was 13 days (range 11–23), 17 days (range 12–53) and 23 days (range 18–70), respectively. We conclude that docetaxel with G-CSF effectively mobilises PBPCs with apheresis needing to be commenced approximately 8 days after docetaxel administration. Bone Marrow Transplantation (2000) 26, 483–487.

Repetitive high-dose therapy with ifosfamide, thiotepa and paclitaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: Results of a phase I study

BACKGROUND This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS The planned treatment was three cycles of high-dose ifosfamide, thiotepa and conventional-dose paclitaxel delivered every 28 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. RESULTS Twenty-three patients were entered into this trial. Of the planned 69 treatment cycles, 59 were delivered and fifteen patients completed all three cycles. The dose-limiting toxicities were renal tubular acidosis, encephalopathy, mucositis and enterocolitis. There was one treatment-related hemorrhagic death. CONCLUSIONS The recommended doses for phase II or III studies are ifosfamide (10 g/m2), thiotepa (350 mg/m2) and paclitaxel (175 mg/m2).

Hodgkin’s disease type Richter’s syndrome in chronic lymphocytic leukemia

The transformation of chronic lymphocytic leukemia (CLL) to large cell lymphoma (Richter’s syndrome) is well described. However, there have been recent reports of Hodgkin’s type Richter’s syndrome (H-RS) in patients with CLL. In this report we describe three additional cases of H-RS transforming from CLL in patients who had been treated for varying periods of time. A summary of patients’ clinical features and outcomes is presented in Table 1. The patients were aged 58–70 years and had been treated for CLL with varying chemotherapy combinations with the onset of H-RS occurring 38–132 months after the diagnosis of CLL. Biopsies which demonstrated H-RS were carried out in all three patients because of clinically progressive disease. Patient GC presented with a retroperitoneal mass and significant weight loss 11 years after the initial diagnosis of CLL; the retroperitoneal mass was biopsied. Thirty-eight months after initial presentation as CLL, patient GM developed immune thrombocytopenia which was refractory to steroids and high-dose gamma globulin; he underwent splenectomy and splenic hilar node biopsy. Patient KB had fever and night sweats in association with progressively increasing generalized lymphadenopathy 10 years after initial presentation of CLL. On CT scanning she also had hepatic and splenic lesions. Fine needle aspiration of the liver lesion and a bone marrow biopsy were carried out. The histopathology was reviewed independently by two pathologists (SJ and DE). The diagnosis of H-RS was made on lymph node biopsy in two patients (GM and GC) and on bone marrow biopsy in one patient (KB). In two patients (GM and GC) with lymph node biopsies, the nodes were 11–22 mm in diameter. There was a diffuse replacement of the lymph node architecture with sheets of small lymphocytes with rounded nuclei and clumped chromatin and scant cytoplasm. There was focal sclerosis. Scattered within this were single cells and clusters of large cells with irregular nuclei, pale vesicular chromatin and large eosinophilic nucleoli; some of the larger cells had abundant amphophilic cytoplasm (Hodgkin’s cells Figure 1). In the third patient (KB) in whom the diagnosis was based on bone marrow biopsy, there was an admixture of histiocytes and fibroblasts among the Hodgkin’s cells; fine needle aspiration of the liver lesion revealed a polymorphic cellular infiltrate including Hodgkin’s cells. On immunohistology, the large Hodgkin’s cells were CD15+, CD30+ and EMA− in all three cases. In case 1 (GC) the background small lymphocytes stained with CD20; in case 2, the larger cells showed positive staining with CD20 but not CD79a; most of the background lymphocytes were CD20-positive, but there were scattered cells which were positive for CD3 and UCHL1. In case 3 (KB) the background cells were positive with CD68 (histiocytes) and CD3 (T cells).

Repetitive high-dose therapy with cyclophosphamide, thiotepa and docetaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer : results of a phase I study

This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). The planned treatment was three cycles of high-dose cyclophosphamide, thiotepa and docetaxel delivered every 35 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. Eighteen patients were entered into this trial. Of the planned 54 treatment cycles, 44 were delivered and 11 patients completed all three cycles. The dose-limiting toxicities were interstitial pneumonitis and mucositis with moderately severe diarrhea (n = 3) and rash (n = 3). There were no treatment-related deaths. Of the 17 patients with evaluable disease, 16 patients responded with six patients achieving a complete remission and an additional four patients achieving no detectable disease (negative re-staging including PET scan) but a persistently abnormal bone scan. At a median follow-up of 12 months, median progression-free survival was 11 months with the median overall survival not reached. The recommended doses for phase II/III studies are cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and docetaxel (100 mg/m2). Bone Marrow Transplantation (2000) 26, 955–961.

Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti-tumor activity in patients with metastatic breast cancer.

For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 μg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6 × 106 CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10–13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs ifosfamide-paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0 × 106/kg per day during days 9–14. After a median of 3 (range 1–5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2 × 106/kg (range 0.16–54.9), 37 × 104/kg (range 5.7–247) and 7.3 × 108/kg (range 2.1–26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity.