Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma.

This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ⩾65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m2. The recommended phase 2 dose was established at 70 mg/m2 and 54 patients (phase 1 and 2) received weekly carfilzomib 70 mg/m2: 85% of them achieved ⩾partial response (PR), 66% ⩾very good PR, 30%⩾near-complete response (CR) and 15% CR. Responses improved in 40 patients who started maintenance: 98% achieved ⩾PR, including 29% CR and 10% stringent CR. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 53.2% and 81%, respectively. The most frequent grade 3-5 toxicities were neutropenia (22%) and cardiopulmonary adverse events (9%). This is the first study of weekly carfilzomib plus an alkylating agent in elderly patients with NDMM. wKCyd was effective, with an acceptable risk/benefit ratio, and thus can be a valid option in this setting.

Primary plasma cell leukemia: a retrospective multicenter study of 73 patients.

BACKGROUND: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. PATIENTS AND METHODS: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). RESULTS: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. CONCLUSIONS: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes.

BU/melphalan and auto-SCT in AML patients in first CR: a 'Gruppo Italiano Trapianto di Midollo Osseo (GITMO)' retrospective study.

AML patients (total 129; median age =50 years; range 16-72) in first CR received BU and melphalan (BU/Mel) as conditioning regimen before auto-SCT. In all, 82 patients (63.6%) received PBSCs and 47 patients (36.4%) received BM cells. The distribution of cytogenetic categories was conventionally defined as favorable (15.5%), intermediate (60.1%) and unfavorable (24.3%). With a median follow-up of 31 months, the 8-year projected OS and disease-free survival (DFS) was 62 and 56% for the whole population, respectively. The relapse rate was 46% and the non-relapse mortality was 4.65%. Although PBSC transplantation led to a faster hematological recovery than BM transplantation, in univariate analysis the stem cell source, cytogenetics and different BU formulations did not significantly affect OS and DFS, whereas age and the number of post-remission chemotherapy cycles did have a significant effect on the clinical outcome. Multivariate analysis identified age <55 years as the only important independent predictor for OS and DFS. Our data suggest that BU/Mel, being associated with a low toxicity profile (mainly mucositis) and mortality, is an effective conditioning regimen even for high-risk AML patients in first CR undergoing auto-SCT.

Fludarabine containing-regimens may adversely affect peripheral blood stem cell collection in low-grade non Hodgkin lymphoma patients.

Fludarabine (FLUDA) based chemotherapy has shown promise in both initial and salvage treatment of low-grade non Hodgkin's lymphomas (LG-NHL). Recently, more aggressive therapies followed by autologous hemopoietic progenitor cell rescue, have also been successfully employed in these patients. However, this procedure, due to several factors including previous therapeutic regimens, is often limited by an inadequate collection of peripheral blood stem cell (PBSC). At present, very little data is available on the effect of FLUDA containing regimens in PBSC collection. We report our preliminary experience showing a possible correlation between FLUDA based chemotherapy regimens employed before mobilization and inability to collect an adequate number of blood derived hematopoietic progenitors for autologous PBSC transplantation in LG-NHL patients.

Clinical outcome of extramedullary plasmacytoma.

BACKGROUND AND OBJECTIVE: The aim of this study was a retrospective analysis of the presenting features of extramedullary plasmacytoma, its response to therapy and its clinical course. DESIGN AND METHODS: Forty-six cases diagnosed between August 1970 and June 1993 were carefully reviewed. The follow-up was continued until June 1998 and the median observation time was 118 months. RESULTS: The disease was most frequently localized in the upper airways (37/46; 80%), with the mass limited to a single site in all but seven patients in whom two contiguous sites were involved. Other localizations were the lymph nodes, thyroid, skin, stomach, and brain. The clinical symptoms were related to the site of presentation, and the median time between appearance and diagnosis was 7.5 months. The median age at diagnosis was 55 years (range 16-80), with 14 patients (30%) being under 50 years old. The disorder was approximately twice as common in males as in females. Ten patients (21%) had a monoclonal component. The therapeutic strategy varied, although the most frequent form of treatment was local radiotherapy. Thirty-nine patients (85%) achieved complete remission (CR), five (11%) a partial remission (PR) and two (4%) did not respond to therapy (NR). Local recurrence (LR) or recurrence at other sites (ROS) occurred in 7.5% and 10%, respectively. Seven patients (15%) developed multiple myeloma (MM), characterized by multiple sites of osteolysis in almost all cases with soft tissue involvement in some of them. The 15 year survival rate was 78%. INTERPRETATION AND CONCLUSIONS: This review of a relatively large series of patients confirms the favorable prognosis of EMP when treated locally by irradiation and/or surgery.

Human herpesvirus 6 infection in autologous bone marrow transplant recipients: a prospective study.

After primary infection in early life, human herpesvirus 6 (HHV-6) remains latent in the body and may reactivate in subjects with poor immune status. A 180-day longitudinal study of HHV-6 infection was carried out in 23 autologous bone marrow transplant recipients to evaluate reactivation of HHV-6; two of these patients underwent a double transplant. The patients were monitored prospectively for HHV-6 DNA in peripheral blood mononuclear cells (PBMC) by hot start nested PCR. Positive samples were typed by the enzymatic restriction protocol. Positive plasma samples were also tested for HHV-6 DNA. Antibodies against HHV-6 were measured by immunofluorescence. Five and two out of 23 patients had intermittent and persistent positivity to HHV-6 DNA in PBMCs, respectively; four patients carried variant B, and the other three patients both A and B. None of the respective plasma samples were positive. Two patients were positive for HHV-6 antibodies. Since the significance of HHV-6 DNA in PBMCs is unclear, these findings do not necessarily indicate active infection but may be due to mild immunosuppression in autologous BMT recipients.

Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

[Lymphomas presenting as Tietze's syndrome: a report of 4 clinical cases]. / Linfomi esorditi come sindrome di Tietze: descrizione di quattro casi clinici.

We describe 4 cases of malignant lymphoma (3 women, 1 man, age range 20-49 years) presenting with a tender and fusiform swelling at the level of the upper costosternal joints, with the clinical characteristics of classic Tietze's syndrome. Physical examination, laboratory findings and chest X-rays all were negative, while telethermography examination evidenced an area of hyperthermia at the level of the swelling in the chondrosternal region. Tietze's syndrome was diagnosed and the patients were treated with non-steroidal anti-inflammatory drugs and a local injection of corticosteroid. The clinical picture did not change, and in 2 cases a cervical lymphadenopathy developed. A biopsy of the lymph nodes and articular tumefaction disclosed Hodgkin's disease in 3 cases and non-Hodgkin's lymphoma in 1 case. Computerized tomography, lymphography and bone marrow biopsy permitted the complete staging of the lymphoma. After beginning a therapeutic program with chemotherapy and irradiation therapy, all 4 patients underwent complete remission.

Behaviour of human lymphocytic isoenzymes of 5'-nucleotidase.

The behaviour of 5'-nucleotidase isoenzymes (ecto-5'-nucleotidase, e-Ns and c-N-II soluble 5'-nucleotidases) was studied in lymphocytes from patients with B-cell chronic lymphocytic leukemia. A strong reduction in ecto- and soluble activities was observed, although the pattern of the three 5'-nucleotidases did not always strictly overlap. A significant decrease (p<0.05) in ecto-5'-nucleotidase, e-Ns and c-N-II was found in B and T populations (B lymphocytes: 1.13, 0.88 and 1.26 nmol/h/10(6) cells versus 95.96, 9.64 and 13.73 nmol/h/10(6) cells in controls; T lymphocytes: 1.31, 0.23 and 0.06 nmol/h/10(6) cells versus 9.25, 1.31 and 2.10 nmol/h/10(6) cells in healthy subjects). The percentage of ecto-5'-nucleotidase-positive cells (CD73+) was reduced in leukemia patients, indicating a lower number of active molecules on the cell surface. The results of RT-PCR analysis showed that the ecto-5'-nucleotidase mRNA of leukemia patients was not defective.

5'-nucleotidase activity in lymphocytes from patients affected by B-cell chronic lymphocytic leukemia.

OBJECTIVES: The activity of membrane-bound ecto-5'-nucleotidase and soluble e-Ns and c-N-II 5'-nucleotidases was evaluated on lymphocytes from patients affected by B-cell chronic lymphocytic leukemia (B-CLL). A statistically significative decrease in ecto-5'-nucleotidase, e-Ns, and c-N-II activities was observed in peripheral blood lymphocytes and in B and T populations from affected individuals. DESIGN AND METHODS: For the assay of ecto-5'-nucleotidase, e-Ns, and c-N-II activity we used a radioactive procedure coupled to HPLC. Since the ecto-5'-nucleotidase is identified as CD73 antigen, we performed immunofluorescence analysis using a specific monoclonal antibody. We analyzed ecto-5'-nucleotidase mRNA by RT-PCR to ascertain the possibility of an alteration in the transcription of its gene. RESULTS: A decrease in ecto-5'-nucleotidase activity was correlated to reduction in ecto-5'-nucleotidase positive cells (CD73+) in leukemia patients. RT-PCR produced a fragment of the expected size and the specific mRNA was found expressed in both healthy subjects and leukemia patients. CONCLUSIONS: The decrease in ecto-5'-nucleotidase activity in patients with B-CLL is not due to loss of transcription of the specific mRNA. The presence of point mutations, splicing alteration, or posttranslational modifications must be investigated. If a defect at DNA or RNA level will be detected, the molecular analysis will be considered for diagnosis of B-cell chronic lymphocytic leukemia.

Expression of the T-cell-specific tyrosine kinase Lck in normal B-1 cells and in chronic lymphocytic leukemia B cells.

Src family kinases play a key role in mitogenesis. The exquisitely tissue-specific distribution of different Src family members suggests that a fine tuning of their expression might be a key prerequisite for cell homeostasis. We tested B cells from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) for expression of Src family kinases. The T-cell-specific tyrosine kinase Lck was found to be expressed at significant levels in CLL B-cells. This finding could be accounted for either by ectopic expression of Lck in B-CLL or by specific expression of this kinase in normal B-1 cells, which are believed to be the normal counterpart of CLL B cells. To answer this question B cells from different sources, characterized by a different size of the B-1 subpopulation, were tested for Lck expression. The results show that Lck expression is a feature of CD5(+), B-1 cells, suggesting a potential role for Lck in the self-renewal capacity of this B-cell subpopulation and supporting the notion that B-1 cells are the subset undergoing oncogenic transformation in B-CLL. Furthermore, we show that the CD5(-), B-2 subpopulation, while normally lacking Lck expression, acquires the capacity to express Lck ectopically upon transformation by EBV.

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

CD4+/CD45RA+ 'naive' T cells and immunological response to influenza virus vaccine in B-cell chronic lymphocytic leukaemia patients.

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by a high frequency of infections, including those of viral aetiology. Previous reports have demonstrated a specific immunologic response to influenza virus vaccine in B-CLL patients with normal IgG levels. In this study, we have evaluated different immunophenotypically defined B and T cell subsets in 18 B-CLL patients before immunization with killed-influenza-virus vaccine. A correlation between immunological response to vaccination and both absolute numbers of CD4+/CD45RA+ naive T cells and CD5- B cells was found. These data may suggest a supporting role of the CD4+/CD45RA+ T cell subset in the specific antibody response to vaccination with influenza virus vaccine in B-CLL patients.

Time-Dependent Kinetics of Tretinoin in Chronic Myelogenous Leukaemia during Intermittent Dose Scheduling: 1 Week On/1 Week Off.

OBJECTIVE: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with Ph1+ chronic myelogenous leukaemia (CML) in the chronic phase. PATIENTS: Eighteen patients with CML were treated with tretinoin 80 mg/m(2)/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). RESULTS: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean +/- SD) 678.3 +/- 498.1 to 258.7 +/- 272.4 microg/L.h. In about 40% of the patients the decline in plasma concentrations was >/=80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t((1/2))) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the noninduced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. CONCLUSION: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.

Uncoupling of T-cell antigen receptor and downstream protein tyrosine kinases in common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestations of the disease and the underlying mechanisms leading to the immunodeficiency. Although the overt defect is an impairment in B-cell function, there is increasing evidence of primary T-cell dysfunctions in a proportion of patients with CVID. We have analyzed T-cells from six CVID patients for activation of both early and late events in response to TCR triggering. The data showed that T-cells from three of six CVID patients were defective in the capacity to initiate the TCR/CD3 signaling pathway by activating intracellular tyrosine kinases, associated with impaired proliferative responses to TCR/CD3 triggering. Since both surface expression of the TCR/CD3 complex and intracellular expression of key tyrosine kinases such as p56lek and ZAP-70 were normal in these patients, our data suggest a defect in the earliest step of TCR signal transduction.

Localized orbital lymphoma.

BACKGROUND AND OBJECTIVE: Localized orbital non Hodgkin's lymphoma is a rare event which has not been reported much in the literature. The aim of this study was to evaluate the clinical features, histology, treatment and clinical outcome of patients with localized orbital lymphoma. METHODS AND RESULTS: Fifteen patients with stage I-E orbital lymphoma diagnosed between 1975 and 1992 were reviewed. Diagnosis was formulated from 3-84 (median 23) months after the appearance of symptoms. Eight patients were males and 7 were females; median age was 55 years. The lacrimal gland was involved in 8 cases, the orbit in 7. Bilateral orbital localization was observed in only one patient. All cases were diagnosed as low-grade MALT lymphoma. Chemotherapy was administered in 7 patients, radiotherapy was employed in 7 and surgical excision was performed in the remaining case. Almost all the patients (14/15; 93%) achieved a complete remission (CR). Local relapse (LR) was observed in 3 cases but disease spread was never recorded. INTERPRETATION AND CONCLUSIONS: Correct histological diagnosis and careful staging are very important for the treatment and outcome of localized low-grade orbital lymphoma. These patients show a very good prognosis and radiation therapy alone is very effective in the treatment of this malignancy.