A Abdul-Hai

Hebrew University of Jerusalem, Yerushalayim, Jerusalem District, Israel

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Publications (26)84.04 Total impact

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    ABSTRACT: Abstract We compared the tolerability and anti-myeloma effect of 2 conditioning regimens for auto-SCT in consecutive groups of patients. Protocol 1 was the earlier and consisted of the combination of 3 agents in a sequential manner including etoposide, thiotepa and melphalan (n=29), while protocol 2 employed melphalan alone (n=34). The 2 groups were comparable (other than younger age in protocol 1). Conditioning with protocol 1 seemed more toxic as expressed by the higher number of febrile days and higher demand for parenteral nutrition. This was not expressed in higher number of admission. With a 108 and 60 months median follow-up respectively, the median survival in patients treated by protocol 2 (melphalan 200mg/m2) was reached at 59 months, while the median survival was not yet reached in patients treated with protocol 1 (p=0.039). The time to progression was significantly longer with protocol 1 (median 44 months vs. 17 months with protocol 2, p=0.033). Confounded by the small number of patients, conditioning with melphalan augmented by etoposide and thiotepa in a sequential manner is slightly more toxic than melphalan alone and may benefit myeloma patients undergoing auto-SCT.
    Leukemia & lymphoma 03/2013; · 2.61 Impact Factor
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    ABSTRACT: The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.
    Bone marrow transplantation 11/2009; 45(7):1189-96. · 3.00 Impact Factor
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    ABSTRACT: Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that is used for psoriasis control. We recently showed its effect in acute steroid-resistant/dependent GVHD. In this study, we describe the effect of alefacept treatment on chronic extensive GVHD (cGVHD). Twelve patients were included in this study; of these 8 (9 of 13 episodes) showed response. The median time to initial response was 2.25 weeks and the response was marked (n=3), moderate (n=2) or minimal (n=4). In two responding patients, the response was only temporary. Complications that appeared during treatment included infection, pericarditis and squamous cell carcinoma of the lip. All these events may be related to other drugs given simultaneously. With a 30-month median follow-up, 6 of 12 patients are alive, with all but one with stable or improved cGVHD. Six patients died because of GVHD progression, whereas none of the patients experienced relapse of the disease for which the transplantation was done. As reported earlier in psoriatic patients treated with alefacept, we found a consistent increase in the percentage of naive T cells as a consequence of treatment. In conclusion, alefacept is effective for the treatment of cGVHD, and dose and time intervals of treatment should be explored further.
    Bone marrow transplantation 11/2008; 43(4):339-43. · 3.00 Impact Factor
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    ABSTRACT: The effect of ABO-incompatibility on transplantation outcome remains a controversial issue, with many of the reported studies showing conflicting results. In this study, we evaluate: the association between ABO-incompatibility and myeloid engraftment; the incidence and severity of acute and chronic graft-versus-host disease (GVHD); non-relapse mortality (NRM); GVHD-associated mortality, relapse and overall survival (OS). Our study includes 221 patients with malignant diseases treated in the same institution with the same reduced intensity regimen. Other variables known to affect the transplantation outcome such as age, disease, disease risk, and donor characteristics were well-balanced between ABO-matched and ABO-mismatched transplants. Analysis of our data shows increased incidence of NRM during the first months after transplantation in the groups of patients with major and minor ABO-incompatibility. Although neither incidence nor severity of GVHD differed significantly among the different groups, we found increased mortality associated with GVHD in the major ABO-incompatible groups. Long-term OS and relapse rate were not different, although we observed a trend for decreased OS during the first year post transplantation in the group of patients with major ABO-incompatibility. Our study showed that ABO-incompatibility has an adverse impact on the transplantation outcome.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2008; 14(4):409-17. · 3.15 Impact Factor
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    ABSTRACT: The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.
    Bone Marrow Transplantation 12/2007; 40(10):957-64. · 3.54 Impact Factor
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    ABSTRACT: The use of thiotepa (TH) is increasing, especially in stem cell transplantation, mainly due to its safety and blood-brain barrier penetration. We evaluated the use of TH in a murine model simulating autologous stem cell transplantation, with or without additional agents. Between 1 and 11 days following inoculation of BALB/c mice with 10(5)-10(8) B-cell leukemia (BCL1) cells (simulating pre-transplant leukemia loads), each group received an 'induction-like' irradiation and/or cytotoxic regimen. Animals were either followed without treatment, or an adoptive transfer (AT) was performed to untreated BALB/c mice. Administered alone without AT, high-dose TH did not change the time to appearance of leukemia. Nevertheless, in the AT experiments, TH as a single agent showed better antileukemic activity than busulfan (BU). Cyclophosphamide (CY)-containing regimens were the most effective, and the TH-CY combination was as effective as the commonly used BU-CY combination, and more effective than the BU-TH combination. Moreover, a synergistic effect was seen in the TH-CY combination (none of the animals developed leukemia, whereas 4/10 animals in the CY-TBI group developed leukemia (P=0.029)). In conclusion, although TH produced only a moderate effect against BCL1 leukemia when used alone, its combination with CY is promising and should be tested further in allogeneic murine models and clinical studies.
    Bone Marrow Transplantation 12/2007; 40(9):891-6. · 3.54 Impact Factor
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    ABSTRACT: The development of reduced intensity or non-myeloablative conditioning (NST) in preparation for allogeneic stem cell transplantation (SCT) revolutionized the field and led to reconsideration of the dogma of upper age limit that was set up by the transplant centers as an eligibility parameter. Analysis of the literature data showed that NST regimens are associated with decreased transplant related mortality, and graft-versus-host disease, in comparison with standard myeloablative conditioning, in patients above the age of 50-55 years, or in younger patients with significant comorbidities. However we have to mention, that our considerations are based on the retrospective analysis of the literature data, and that well controlled prospective randomized studies are needed in order to definitely assess the role of NST. Comorbidity indices might be proved as the most important parameters for the choice of the most proper regimen for each patient in need and should be included in future trials.
    Critical Reviews in Oncology/Hematology 11/2007; 64(1):49-63. · 4.64 Impact Factor
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    ABSTRACT: Interleukin-7 (IL-7) plays a key role in maturation and function of both T and B cells. We investigate the potential use of recombinant human IL-7 for facilitation of graft-versus-leukemia (GVL) effects mediated by T cells following transplantation in a murine model. Administration of IL-7 in vivo to allogeneic-transplanted mice improved disease-free survival: 67% of mice treated with IL-7 remained alive and disease free for more than 60 days, in comparison to 17% of the controls (P<0.05). Similar results were obtained when C57BL/6 spleen cells sensitized against irradiated B-cell leukemia (BCL(1)) cells in the presence of IL-7 were transplanted to F(1) mice, followed by IL-7 treatment in vivo. Of the BALB/c mice that received spleen cells from F(1) mice treated with IL-7 following transplantation of C57BL/6 spleen cells sensitized with irradiated BCL(1) in the presence of IL-7, only 29% developed leukemia, as compared to 79% in the control group (P<0.05). Mice treated with IL-7 showed increased splenic and thymic cellularity and improved T cell-dependent proliferative responses compared to the controls (P<0.05). IL-7 may provide a novel tool to enhance immune reconstitution following transplantation of mismatched stem cells and for enhancement of GVL effects mediated by alloreactive lymphocytes.
    Bone Marrow Transplantation 11/2007; 40(9):881-9. · 3.54 Impact Factor
  • Leukemia Research - LEUK RES. 01/2007; 31.
  • Leukemia Research - LEUK RES. 01/2007; 31.
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    ABSTRACT: Success of allogeneic and autologous bone marrow transplantation (BMT) is hampered by susceptibility to infection during the first two post-treatment years. Further, in treating malignant diseases, impaired anti-host reactivity for donor cells may contribute to a high rate of relapse. Both complications are a consequence of immune deficiency involving B and T lymphocytes. The present study evaluates several key parameters of the immunologic reconstitution mechanism in mice subjected to myeloablative total body irradiation following semi-allogeneic (parental) BMT. This resulted in a gradual reduction of splenic CD3, CD4 and CD8 cells until day 45 post-BMT. Concomitantly, there was an increase in monocytes and CD4+/CD8+ (double positive) cells, accompanied by a persistent elevation in the percentage of B lymphocytes. The total thymic and splenic T cell populations were reduced until day +30. The cellular reduction correlated with the poor proliferative response of the thymic and splenic cells. A decrease occurred in IL-2 mRNA expression in thymic cells during days 15-20 post-transplant, corresponding with the low level of IL-2 secretion in the spleen and thymus of the transplanted mice. In conclusion, following semi-allogeneic BMT, there was an overall immune down-regulation in the cells, gene and protein levels. Reduced immunological responsiveness following BMT reinforces the need for improving the immune dysfunction by immunotherapy post-BMT.
    Cancer Immunology and Immunotherapy 12/2006; 55(11):1330-6. · 3.64 Impact Factor
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    ABSTRACT: Hemorrhagic cystitis (HC) is a well-known complication of HSCT. Its overall incidence has been reported to vary from 7-68%. The spectrum of clinical presentation varies from asymptomatic microhematuria to life-threatening bleeding. Sodium hyaluronate is a glycosaminoglycan present on the bladder mucosa, which serves as an important protective substance against uroepithelial damage. Preparations of this component have been shown to be effective in the treatment of interstitial cystitis. We report our experience in the treatment of post-transplant HC with intravesical instillation of sodium hyaluronate. Five out of the seven patients included in this study achieved complete response, while one patient had only partial response. Sodium hyaluronate administration was not associated with any local or systemic adverse effects. We consider that the results of our study are promising and the efficacy of sodium hyaluronate in the treatment of post-transplant HC should be tested in larger cohorts of patients.
    Bone Marrow Transplantation 11/2006; 38(7):507-11. · 3.54 Impact Factor
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    ABSTRACT: We reviewed our experience in the treatment of 13 patients with severe acquired aplastic anaemia, using a newly developed non-myeloablative regimen consisting of fludarabine (total dose 180 mg/m2), cyclophosphamide (total dose 120 mg/kg), and antithymocyte globulin (total dose 40 mg/kg). All except one patient received multiple transfusions and had failed prior immunosuppressive treatment. Twelve out of 13 patients achieved sustained engraftment. One patient was not evaluable for engraftment because of early death on day +10. None of the patients developed graft failure. Mucositis of mild-to-moderate severity was the only observed regimen-related toxicity. The cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV and III-IV was 8.3% and 0%, respectively. With a median follow-up period of 45 months, the 5-year overall survival probability was 84%. Eight out of 11 surviving patients have been followed for more than 1 year and only one developed limited chronic GvHD. All patients enjoy a normal life style, with a Karnofsky score of 100%, and all except three, followed for 3, 5 and 6 months respectively, are free of any immunosuppressive medication. The results of this study look promising, while prospective clinical trials may be required to confirm the benefits of this regimen as an alternative to existing protocols.
    British Journal of Haematology 07/2006; 133(6):649-54. · 4.94 Impact Factor
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    ABSTRACT: Graft-vs-host disease (GVHD) is still the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). On the one hand, it predisposes transplant recipients to risk of bacterial, fungal, and viral infections, on the other, lipopolysaccharide (LPS), an endotoxin found in the cell walls of gram-negative bacteria, has been shown to play a significant role in the development and severity of GVHD following allogeneic myeloablative BMT. Our study focused on immunization of recipient and donor mice with endotoxin prior to transplantation, in an attempt to reduce mortality caused by gram-negative bacterial infections posttransplantation. In one experiment, recipient mice were immunized with LPS prior to BMT, whereas in another experiment, donor mice were immunized prior to BMT. The mice were evaluated for development of GVHD and for survival. Our results showed that injection of low-dose LPS to mice prior to induction of GVHD with allogeneic spleen cells saved more than 40% of the recipients, whereas all mice in the untreated control group died. The survival of recipients of spleen cells from immunized donors rose to 54% and clinical signs of GVHD were attenuated as compared to control mice inoculated with spleen cells obtained from unimmunized donors. This immunization protocol suggests that immunization of the donor or the recipient against LPS prior to transplantation may be protective against gram-negative bacteria.
    Experimental Hematology 05/2006; 34(4):549-53. · 2.91 Impact Factor
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    ABSTRACT: Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmyeloablative conditioning. GVL effects can be amplified by post-grafting donor lymphocyte infusion (DLI). Unfortunately, DLI is frequently associated with graft-versus-host disease (GVHD). We investigated the feasibility of induction of potent GVL effects by DLI using intentionally mismatched lymphocytes followed by elimination of alloreactive donor T cells by cyclophosphamide for prevention of lethal GVHD following induction of very short yet most potent GVL effects. Mice inoculated with B-cell leukemia (BCL1) and mismatched donor lymphocytes were treated 2 weeks later with low-dose or high-dose cyclophosphamide. All mice receiving cyclophosphamide 2 weeks after DLI survived GVHD, and no residual disease was detected by PCR; all control mice receiving DLI alone died of GVHD. Analysis of host (female) and donor (male) DNA showed that cyclophosphamide treatment eradicated most alloreactive donor cells, yet mixed chimerism was converted to full donor chimerism following transient self-limited GVHD. Our working hypothesis suggests that short-term yet effective and safe adoptive immunotherapy of leukemia may be accomplished early post-transplantation using alloreactive donor lymphocytes, with prevention of GVHD by elimination of GVL effector cells.
    Cancer Research 12/2005; 65(21):9735-40. · 8.65 Impact Factor
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    ABSTRACT: Linomide (quinoline-3-carboxamide) is an immunomodulator with anti-inflammatory effects in rodents with autoimmune diseases. Its mode of action still remains to be elucidated. We hypothesized that an investigation of T cell interactions with the extracellular matrix (ECM), composed of glycoproteins such as fibronectin (FN) and laminin (LN), might provide better understanding of their in vivo mode of action in extravascular inflammatory sites. We examined the effect of Linomide on T cell adhesion to intact ECM, and separately to LN, and FN, and on the release and production of tumor necrosis factor (TNFalpha) and nitrogen oxide (NO) in relation to adhesive molecules in non-obese diabetic (NOD) female spleen cells, focusing on intracellular adhesion molecule-1 (ICAM-1) and CD44. NOD female mice that developed spontaneous autoimmune insulitis, which destroys pancreatic islets and subsequently leads to insulin-deficient diabetes mellitus, were studied. Linomide, given in the drinking water or added to tissue cultures in vitro, inhibited the beta1 integrin-mediated adhesion of T cells to ECM, FN and LN, as well as the production and release of TNFalpha and NO, which play a major role in the induction and propagation of T cell-mediated insulitis. In addition, exposure of T cells to Linomide resulted in increased expression of CD44 and ICAM-1 molecules on spleen cells of Linomide-treated mice; such an increase in adhesion molecule expression may lead to more effective arrest of T cell migration in vivo. The regulation of T-cell adhesion, adhesion receptor expression, and inhibition of TNFalpha and NO secretion by Linomide may explain its beneficial role and provide a new tool for suppressing self-reactive T cell-dependent autoimmune diseases.
    International Immunopharmacology 03/2005; 5(2):231-9. · 2.42 Impact Factor
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    ABSTRACT: Allogeneic stem cell transplantation (SCT) is the treatment of choice for a large number of hematologic malignancies. Its major advantage over conventional chemotherapy lies in the graft-versus-leukemia (GVL) effects mediated by allo- or tumor-reactive donor lymphocytes given in the course of SCT or post transplantation as donor lymphocyte infusions (DLI). The benefits of cell-mediated immunotherapy over myeloablative radiochemotherapy have also made it possible to reduce the intensity of conditioning regimens. Mobilized peripheral blood has proved preferable to bone marrow (BM) as a source of stem cells for transplantation, since it provides a larger number of stem cells on the one hand and immunologically competent lymphocytes on the other. The use of granulocyte colony stimulating factor (G-CSF), which is necessary to mobilize and increase the number of stem cells, may down-regulate the GVL effect by suppression of donor effector T lymphocytes by inducing Th1-->Th2 cytokine switch. It has previously been shown that GVL effects may be amplified by both in vivo and in vitro activation of donor lymphocytes with human recombinant interleukin-2 (rIL-2). Our studies using a leukemic murine model prepared for transplantation with low intensity conditioning prior to infusion of G-CSF-mobilized peripheral blood stem cells (PBSC) have demonstrated that mobilization of blood cells with G-CSF and in vivo treatment with rIL-2 following low-intensity conditioning enhances the GVL effects and prolongs survival of recipients inoculated with BCL1. Activation of donor lymphocytes with rIL-2 may thus be useful for amplifying GVL effects following mobilization with G-CSF.
    Cancer Immunology and Immunotherapy 04/2004; 53(4):358-62. · 3.64 Impact Factor
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    ABSTRACT: Donor lymphocyte infusion mediates most effective graft- versus-leukemia (GVL) effects following induction of host-versus-graft tolerance by transplantation of donor stem cells. This study was designed to maximize GVL effects across both major (MHC) and minor (mHgs) histocompatibility barriers in recipients inoculated with murine B-cell leukemia (BCL1), using specifically immune donor lymphocytes. GVL effects were induced with donor spleen cells from mice immunized across MHC or mHgs barriers with BCL/1 cells or normal BALB/c spleen cells. Our data suggest that spleen cells from donor mice immunized against murine B-cell leukemia of BALB/c origin, or to a lesser extent against normal host alloantigens, induce better therapeutic GVL effects with less great-versus-host disease (GVHD) across both mHgs and MHC. The cytokine profile of effector cells inducing predominantly GVL effects with reduced GVHD across MHC and mHg barriers consisted preferentially of upregulated IFN-gamma, IL-2, IL-10 and IL-12 in donors, implying a Th-1 to Th-2 cytokine shift. We hypothesize that immunotherapy with immune donor lymphocytes sensitized in vivo or in vitro with allogeneic tumor cells or normal host cells together with allogeneic BMT may provide an effective approach for amplifying GVL effects, while reducing procedure-related morbidity and mortality due to uncontrolled GVHD.
    Bone Marrow Transplantation 10/2003; 32(5):495-504. · 3.54 Impact Factor
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    L Weiss, A Abdul-Hai, R Or, G Amir, A Polliack
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    ABSTRACT: Graft-versus-host disease (GVHD) is a severe disorder and despite therapeutic efforts to decrease its distressing clinical manifestations, treatment is still not optimal. Here we report the results of studies, in which the purine analogue, fludarabine phosphate, was used in an attempt to modify and decrease GVHD after stem cell transplantation, across major histocompatibility barriers for murine leukemia. B-cell leukemia (BCL-1) bearing (BALB/c x C57BL/6) F1 mice received two cycles of fludarabine (0.8 mg/kg) for 5 days every 2 weeks, followed by 400 mg/kg cyclophosphamide i.p. Animals were then transplanted with C57BL/6 precursor cells and the development of leukemia and extent of GVHD was monitored both clinically and histopathologically. In the fludarabine-treated group, only nine of 28 (32%) mice developed leukemia, compared to 25 of 33 (76%) of control animals (P=0.0006 ). Mice treated with fludarabine-containing regimens prior to transplantation also had much less GVHD both clinically and at autopsy, while graft-versus-leukemia appeared to be augmented in the same animals.
    Bone Marrow Transplantation 02/2003; 31(1):11-5. · 3.54 Impact Factor
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    ABSTRACT: The effect of linomide, an immunomodulatory drug, on natural killer (NK) cells and T cell-dependent immune responses following syngeneic or allogeneic bone marrow transplantation (BMT) was investigated in BALB/c mice inoculated with B-cell leukemia (BCL1). Linomide given in the drinking water had no impact on graft survival or graft versus leukemia (GVL) effects. Although linomide regulates anti-self reactivity in mice with experimental and spontaneous autoimmune disorders, the anti-tumor effects induced by allogeneic donor lymphocytes were not affected. This indicates that different mechanisms regulate anti-self and anti-leukemia effects. Alternatively, linomide might affect the homing of self-reactive lymphocytes to specific target organs in autoimmune disorders, although the homing process may not be relevant to the control of leukemia by alloreactive lymphocytes.
    Cancer Immunology and Immunotherapy 01/2003; 51(11-12):596-602. · 3.64 Impact Factor