[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m(2)) for 4 days followed by one dose of GO 9 mg/m(2) on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31-63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3-4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3-4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy.
Annals of Hematology 10/2014; · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.
British Journal of Haematology 05/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989-93 and 1999-2003.
The Israel Medical Association journal: IMAJ 04/2014; 16(4):224-8. · 0.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.
Annals of Hematology 03/2014; · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract FDG-PET/CT scanning is often used for staging and response assessment in Mantle cell lymphoma (MCL); however, the ability of interim and post therapy scans to predict outcome is debatable. We retrospectively evaluated the prognostic impact of interim and post therapy FDG-PET/CT scan on outcome of patients with MCL. Fifty eight consecutive patients diagnosed between 1998 and 2011 were included in the analysis. Scans, performed at diagnosis, mid-therapy, post chemotherapy (prior to ASCT) and post transplantation, were reviewed and outcome was analyzed. Median age was 59. Most patients presented with advanced disease. MIPI was low in 45%, intermediate in 41% and high in 14%. Thirty four patients (58%) received RCHOP or RCHOP-like chemotherapy and 24 (42%) underwent an upfront ASCT. Three years overall (OS) and progression free survival (PFS) were 81% and 45% respectively. No significant differences in OS or PFS between the PET positive and PET negative groups both for interim and post therapy scans were observed. Analysis of chemotherapy only and chemotherapy+ASCT groups separately did not reveal any correlation between interim, post therapy or pre transplant PET result to OS and PFS. We conclude that in patients treated with R-CHOP-21 or R-CHOP- like chemotherapy using the International Harmonization Project criteria to determine whether a scan is positive or negative, there is no role for interim or post therapy PET.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo. EXPERIMENTAL DESIGN: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in NHL cell lines and primary samples from BM aspirates of NHL patients. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with BM involvement. RESULTS: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells. Primary BMSCs further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, while BKT140 abrogated this protective effect. Furthermore, BKT140 demonstrated efficient anti-lymphoma activity in vivo in the xenograft model of disseminated NHL with BM involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the BM. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the BM, achieving 93% reduction. CONCLUSIONS: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab, and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL.
Clinical Cancer Research 05/2013; · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (alloSCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity (RTC) regimens are increasingly used in the last decade, however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given alloSCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95%CI, 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4, and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (HR 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95%CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.Leukemia accepted article preview online, 17 October 2012; doi:10.1038/leu.2012.299.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
NL is defined as infiltration of nerves by malignant cells of lymphocyte origin presenting as a rare extra-nodal manifestation of lymphoma. About 50% of NL was diagnosed prior to PET-CT development, at autopsy. Yet, even since then only sporadic cases of NL were reported. We present a retrospective study of 9 lymphoma patients group with NL diagnosed by PET/CT either at presentation or upon disease recurrence,at our institution.
METHOD AND MATERIALS
During 2004-2010 period, 9 patients (age range 23-69); mean 50 yrs, including 5 females and 4 males were evaluated. 7/9 patients had diffuse large B-cell lymphoma (DLBC) and 2/9- Hodgkin’s lymphoma, transformed to DLBC, who underwent PET CT .A whole body PET-CTwas performed 50` post i.v. injection of 10 mCi F-18-FDG, using 16 slices Helical CT (GXL Philips,LTD). Disease staging, treatment monitoring and follow-up was performed .Their PET-CT findings were correlated with clinical findings, other pertinent diagnostic modalities (MRI,US) and clinical follow-up of up to 6 years.
Most typical NL visualization on 18F-FDG PET-CT scan was a linear shaped uptake pattern along the corresponding thickened nerve tract or neural plexus; or a linear uptake finding simulating the course of a neural tract location. These NL findings were located in extra nodal sites, mostly involving multiple cranial or peripheral nerves, nerve roots at different vertebral levels, or branchial and lumbar plexsuses. These findings frequently accompanyed nodal disease recurrence, necessitating specific attention with early changes in this aggressive disorder management. There were no falsely diagnosed NL results in our group. The appearance of the findings often resembled vascular , lymphatic or muscular tract but anatomic CT localizations aided in identifying their correct nature and locations and as a viable neural disease.
F-l8 FDG PET-CT in our lymphoma group appears to be a highly sensitive and specific in the disgnosis of NL. It has been more frequently diagnosed in recent years, due to increased awareness and extensive use of hybrid PET-CT, enabling anatomic as well as hypermetabolic processes localization in neural structures. Early recognition and treatment of this rare lymphoma manifestation indeed improved disease outcome in our group.
Early recognition and treatment of NL, a rare lymphoma manifestation, indeed improves disease outcome in lymphoma patients.
Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 11/2011
[Show abstract][Hide abstract] ABSTRACT: Bone marrow homing and engraftment by clinically transplanted hematopoietic stem and progenitor cells is a complex process that is not fully understood. We report that the pan-leukocyte CD45 phosphatase plays an essential role in trafficking and repopulation of the bone marrow by immature human CD34(+) cells and leukemic cells in transplanted nonobese diabetic severe combined immunodeficient mice. Inhibiting CD45 function by blocking antibodies or a CD45 inhibitor impaired the motility of both normal and leukemic human cells. Blocking CD45 inhibited homing and repopulation by immature human CD34(+) cells as well as homing of primary patient leukemic cells. In addition, CD45 inhibition negatively affected development of hematopoietic progenitors in vitro and their recovery in transplanted recipients in vivo, revealing the central role of CD45 in the regulation of hematopoiesis. Moreover, CD45 blockage induced a hyperadhesive phenotype in immature human progenitor cells as well as in murine leukocytes, leading to their defective adhesion interactions with endothelial cells. This phenotype was further manifested by the ability of CD45 blockage to prevent breakdown of adhesion interactions in the BM, which inhibited murine progenitor mobilization. The substantial effects of a direct CD45 inhibition point at its essential roles in cell trafficking, including murine progenitor cell mobilization and both normal immature and leukemic human hematopoietic cells as well as regulation of hematopoiesis and engraftment potential.
[Show abstract][Hide abstract] ABSTRACT: Rearrangements of the MLL (ALL1) gene are very common in acute infant and therapy-associated leukemias. The rearrangements underlie the generation of MLL fusion proteins acting as potent oncogenes. Several most consistently up-regulated targets of MLL fusions, MEIS1, HOXA7, HOXA9, and HOXA10 are functionally related and have been implicated in other types of leukemias. Each of the four genes was knocked down separately in the human precursor B-cell leukemic line RS4;11 expressing MLL-AF4. The mutant and control cells were compared for engraftment in NOD/SCID mice. Engraftment of all mutants into the bone marrow (BM) was impaired. Although homing was similar, colonization by the knockdown cells was slowed. Initially, both types of cells were confined to the trabecular area; this was followed by a rapid spread of the WT cells to the compact bone area, contrasted with a significantly slower process for the mutants. In vitro and in vivo BrdU incorporation experiments indicated reduced proliferation of the mutant cells. In addition, the CXCR4/SDF-1 axis was hampered, as evidenced by reduced migration toward an SDF-1 gradient and loss of SDF-1-augmented proliferation in culture. The very similar phenotype shared by all mutant lines implies that all four genes are involved and required for expansion of MLL-AF4 associated leukemic cells in mice, and down-regulation of any of them is not compensated by the others.
Proceedings of the National Academy of Sciences 05/2011; 108(19):7956-61. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chemokine CXCL12 is essential for the function of hematopoietic stem and progenitor cells. Here we report that secretion of functional CXCL12 from human bone marrow stromal cells (BMSCs) was a cell contact-dependent event mediated by connexin-43 (Cx43) and Cx45 gap junctions. Inhibition of connexin gap junctions impaired the secretion of CXCL12 and homing of leukocytes to mouse bone marrow. Purified human CD34(+) progenitor cells did not adhere to noncontacting BMSCs, which led to a much smaller pool of immature cells. Calcium conduction activated signaling by cAMP-protein kinase A (PKA) and induced CXCL12 secretion mediated by the GTPase RalA. Cx43 and Cx45 additionally controlled Cxcl12 transcription by regulating the nuclear localization of the transcription factor Sp1. We suggest that BMSCs form a dynamic syncytium via connexin gap junctions that regulates CXC12 secretion and the homeostasis of hematopoietic stem cells.
[Show abstract][Hide abstract] ABSTRACT: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control.
Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD.
Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01).
These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.
Annals of Oncology 07/2009; 21(1):126-32. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms governing hematopoietic progenitor cell mobilization are not fully understood. We report higher membrane type 1-MMP (MT1-MMP) and lower expression of the MT1-MMP inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), on isolated circulating human CD34+ progenitor cells compared with immature BM cells. The expression of MT1-MMP correlated with clinical mobilization of CD34+ cells in healthy donors and patients with lymphoid malignancies. Treatment with G-CSF further increased MT1-MMP and decreased RECK expression in human and murine hematopoietic cells in a PI3K/Akt-dependent manner, resulting in elevated MT1-MMP activity. Blocking MT1-MMP function by Abs or siRNAs impaired chemotaxis and homing of G-CSF-mobilized human CD34+ progenitors. The mobilization of immature and maturing human progenitors in chimeric NOD/SCID mice by G-CSF was inhibited by anti-MT1-MMP treatment, while RECK neutralization promoted motility and egress of BM CD34+ cells. BM c-kit+ cells from MT1-MMP-deficient mice also exhibited inferior chemotaxis, reduced homing and engraftment capacities, and impaired G-CSF-induced mobilization in murine chimeras. Membranal CD44 cleavage by MT1-MMP was enhanced following G-CSF treatment, reducing CD34+ cell adhesion. Accordingly, CD44-deficient mice had a higher frequency of circulating progenitors. Our results reveal that the motility, adhesion, homing, and mobilization of human hematopoietic progenitor cells are regulated in a cell-autonomous manner by dynamic and opposite changes in MT1-MMP and RECK expression.
The Journal of clinical investigation 03/2009; 119(3):492-503. · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism is a well-recognized and relatively frequent complication of malignancy, whereas tumor thrombosis is a rare complication of solid cancers. The correct diagnosis of tumor thrombosis and its differentiation from VTE can alter patient management and prevent unnecessary long-term anticoagulation treatment.
To evaluate the contribution of 18F-fluorodeoxyglucose positron emission tomography/computed tomography to the diagnosis of tumor thrombosis and its differentiation from VTE.
PET/CT scans from 11 patients with suspected tumor thrombosis were retrospectively evaluated. Suspicion arose from positive PET/CT in eight cases, or from findings on contrast-enhanced CT in three patients. Criteria for positivity of PET/CT included increased focal or linear uptake of 18F-FDG in the involved vessel. Findings were categorized as PET/CT positive, or PET/CT negative and compared to contrast-enhanced or ultrasound Doppler, pathology where available, and clinical follow-up.
Eight occult tumor thromboses were identified by PET/CT-positive scans. Underlying pathologies included pancreatic, colorectal, renal cell, and head-neck squamous cell carcinoma, as well as lymphoma (4 patients). Three thrombotic lesions on contrast-enhanced CT were PET/ CT negative, due to VTE (2 patients) and leiomyomatosis. Accuracy of PET/CT to differentiate between tumor thrombosis and benign VTE was 100% in this small study.
Contrast-enhanced CT defines the extent of thrombotic lesions, while the functional information from PET/CT characterizes the lesions. It appears that PET/CT may be helpful in the diagnosis of occult tumor thrombosis and its differentiation from VTE.
The Israel Medical Association journal: IMAJ 03/2009; 11(2):69-73. · 0.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Positron emission tomography (PET) with F-18 fluorodeoxyglucose detects active lymphoid tissue during HIV-1 infection, with distinct patterns of lymphoid activation correlating to various stages of disease activity. Patients with HIV-1 are at risk for lymphoma, making the differential diagnosis between benign and malignant lymphadenopathy imperative. This study retrospectively evaluated the role of PET/computed tomography (CT) in differentiating active lymphoma from persistent generalized lymphadenopathy in patients with HIV-1.
Seven patients with HIV-1 underwent PET/CT. Six, with known non-Hodgkin lymphoma underwent a total of 16 PET/CT scans; 5/16 scans were performed for initial staging, and 10/16 for evaluating treatment response and follow-up. One patient was referred for evaluation of lymphadenopathy suspected of being lymphoma. PET/CT findings were compared with concurrent clinical, immunologic, and virological data.
PET/CT accurately depicted the extent of lymphoma in 12/16 patients' scans (75%), yet in 4/16 (25%) scans increased fluorodeoxyglucose uptake was noted in lymph nodes of normal CT appearance (PET+/CT-). Viral loads ranged from 0 to 84,000 copies/mL, CD4 T-cell count ranged from 130 to 474 cells/muL in the group. The highest values of both laboratory parameters were concurrent with the discrepant PET+/CT- scans, seen in 4 scans, in 2 patients. The PET+/CT- findings in both these patients were observed in neck, axillae, mediastinum, spleen, and inguinal regions, and sample biopsies of the PET (+) nodes consequently proved benign findings in both patients. All PET+/CT+ findings correctly indicated lymphoma status, as proven by clinical follow-up.
PET/CT accurately detected lymphoma in patients with HIV-1 and had been used confidently as a management tool in this patient group. In the context of discrepant PET/CT findings, increased viral loads and CD4 levels may imply benign HIV-related lymphadenopathy.
Clinical nuclear medicine 10/2008; 33(9):610-4. · 3.92 Impact Factor