Pia Raanani | Tel Aviv University (original) (raw)
Papers by Pia Raanani
Ash Annual Meeting Abstracts, Nov 16, 2004
ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), al... more ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), although about 40% of patients relapse or do not respond to initial treatment. Recently, the HD9 trial of the German Hodgkin’s Lymphoma Study Group has shown that escalated (esc) BEACOPP regimen can achieve better disease control than ABVD, but has a high incidence of acute and long-term toxicities including high occurrence of AML/MDS. In an attempt to decrease toxicity while preserving the potential benefit of upfront intensive therapy, we conducted a pilot study, which tested the feasibility, toxicity and efficacy of combined escBEACOPP-ABVD regimen as therapy for newly diagnosed patients with high risk (IPS≥3) stage III–IV HL. Patients initially received 2 cycles of escBEACOPP followed by reevaluation with CT and gallium or PET/CT-FDG scans. When complete response (CR) or partial response (PR) was achieved, patients continued to receive 4 cycles of ABVD, while those failing to achieve a response were withdrawn from the study. Since August 2001, 21 patients entered the study and at the time of present analysis four of them are still receiving therapy. Three (18%) of 17 patients, who completed chemotherapy, received consolidative radiotherapy. Median age at diagnosis was 26 years (range 18–56) and 11 (57%) were males. Stage IV and B symptoms were evidenced in 19 (90%) and 17 (81%), respectively, and 7 (33%) had bulky mediastinal mass. Histology included nodular sclerosis in 18 patients (86%), mixed cellularity in 2 (10%) and lymphocyte predominance in 1 (5%). Following the first 2 cycles of escBEACOPP the overall response rate (CR+PR) was 100%. At the end of all therapy 15 patients (88%) were in CR, one patient in PR and only a single patient had progressive disease. With a median follow-up of 20 months no patient relapsed or died. Toxicity included WHO grade III–IV granulocytopenia in 15 patients (88%) and grade III–IV infection in one patient. Hospitalization for intravenous antibiotics was necessary in 10 patients (59%). Almost all of these events occurred during the first two cycles of escBEACOPP, while acute toxicity during the ABVD phase was mild. In conclusion, the combined escBEACOPP-ABVD regimen is well tolerated and is associated with a high CR rate when used in advanced HL patients with high IPS scores. Further follow-up is obviously required in order to determine long-term survival and late complications of this regimen.
The Israel Medical Association Journal Imaj, Mar 1, 2012
Leukemia & lymphoma, Jan 16, 2016
Randomized clinical trials that compared chlorambucil to different regimens, for patients with ch... more Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of lo...
Proceedings of the National Academy of Sciences, 2015
Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tum... more Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow o...
Cardio-Oncology, 2015
Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myel... more Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs' safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.
Blood, Nov 15, 2013
Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-ri... more Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL). Protocol The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006]. Results As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant). Conclusions These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.
Ash Annual Meeting Abstracts, Nov 16, 2005
Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Alth... more Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Although it is generally accepted that therapy of the myeloabelative range is related with a high rate of fertility loss, we observed during the last years eight spontaneous pregnancies with normal deliveries in young women after bone marrow transplantation. Seven patients (pt’s) were with lymphoma and MM and were conditioned with BEAM regimen (n=6) and melphalan 200mg/sm (n=1) prior to an autologous SCT, while one patient had a secondary AML and underwent BEAM primed autologous SCT and Busulfex/FA primed allogeneic BMT. The median age at transplant of this group was 28y and median time from transplant to pregnancy was 25 months. More than 100 women of 18–40y.o were transplanted in our center during this period; however, obviously the fertility rate cannot be calculated as it is related with additional parameters including survival, post transplant complications and mainly patient’s preferences. Naturally we observed during the same period many young patients with ovarian failure post transplant, as well as one successful pregnancy from a cryopreserved embryo. Methods. We Therefore initiated in October 2000 a fertility preservation program in which all women of 18 – 40y.o were offered a pretransplant IVF with embryo preservation, and/or ovarian tissue cryopreservation (OTC), according to their clinical status. 651 pt’s were transplanted in our center in the last 44 months, of which 81 were women of 18–41y.o that were all enrolled in this program. Results. Seven pt’s of this group (8.6%) underwent IVF. The major causes of denying IVF were the need to delay BMT for more than clinically accepted, prolonged preexisting ovarian failure, lack of a suitable partner and patient’s preference. Seventeen pt’s (21%) underwent OTC. The major causes of denying OTC were patient’s preference (mainly due to no evidence of success with this method) and thrombocytopenia/neutropenia. During this period: One patient of this group was fertilized with her cryopreserved embryos 32 months after transplant and is at her 16 week of pregnancy. One patient underwent a successful transplantation of her cryopreserved ovarian tissue 2.5 years after HDC while in a documented ovarian failure, and gave birth to a healthy baby on June 2005. The OTC of this patient was performed after cis-platinum containing salvage therapy for relapsing NHL, prior to BEAM primed SCT, and immediately after a failure of hormonal stimulation for IVF. One patient underwent a cryopreserved ovarian tissue transplantation on July 2005 Conclusions: 1. Spontanous pregnancy after HDT, mainly at the younger age, is not a rare phenomenon. 2. Most young patients prior to HDT are not eligible for IVF. 3. Pretransplant ovarian tissue cryopreservation is a feasible tool in this set-up. The first success with this method is promising.
Leukemia Research, 2015
Immunoparesis serves as a marker for elevated risk for progression in plasma cell proliferative d... more Immunoparesis serves as a marker for elevated risk for progression in plasma cell proliferative disorders. However, the impact of immunoparesis in AL amyloidosis has not been addressed. Immunoparesis was defined qualitatively as any decrease below the low reference levels of the uninvolved immunoglobulins and quantitatively, as the relative difference between the uninvolved immunoglobulins and the lower reference values. Forty-one newly diagnosed AL amyloidosis patients were included. Sixty-six percent of patients had a suppression of the uninvolved immunoglobulins. The median relative difference of the uninvolved immunoglobulins was 18% above the low reference levels [range (-71%)-210%]. Ninety percent of the patients were treated with novel agents-based regimens, mostly bortezomib-containing regimens. Nineteen percent of the patients did not attain response to first line treatment. Patients with relative difference of uninvolved immunoglobulins below -25% of the low reference levels were less likely to respond to first line treatment compared to patients with a relative difference of -25% and above [odds ratio for no response vs. partial response and better 30 [(95% CI 4.1-222.2), P=0.0004]. Patients who failed first line treatment were successfully salvaged with lenalidomide-based treatment. Immunoparesis, if assessed quantitatively, may serve as a predictor of response in AL amyloidosis patients treated with bortezomib-containing regimens.
Acta Haematologica, 2015
With the achievement of excellent results with tyrosine kinase inhibitors (TKIs), the next step w... more With the achievement of excellent results with tyrosine kinase inhibitors (TKIs), the next step was to conduct clinical trials aimed at stopping the treatment of patients on these drugs, namely, achieving a ‘cure’ or, alternatively, an ‘operational cure’. The pilot study on 12 CML patients was carried out by the pioneering group from Bordeaux led by Francois Mahon and it provided a proof of concept that imatinib discontinuation could be employed [4] . Since then, nearly 1,000 CML patients around the world have officially stopped using TKIs [5] . These studies gave answers to some of the questions raised regarding treatment discontinuation, such as the estimated rate of sustained molecular remission, factors predicting for prolonged molecular remission, the safety of discontinuing TKIs and the timing of molecular relapse after discontinuation. Yet, many issues remain open. These include the criteria for stopping TKIs – i.e. the depth and duration of molecular remission before discontinuation, the standardization of follow-up, i.e. the molecular threshold that triggers retreatment as well as the schedule and intensity of molecular follow-up after discontinuation. Last but not least, what place is there for treatment cessation outside of a clinical trial? Most studies have been conducted on patients who have achieved molecular remission in the range of a 4–4.5 First staged in 1895 in London, the play ‘The Importance of Being Earnest’, written by Oscar Wilde, challenged the social obligations of Victorian London society. One hundred and ten years later, also in London, the importance of being cured of chronic myeloid leukemia (CML) was challenged by the late Professor John Goldman, who coined the term ‘operational cure’ [1] . In one of his last publications, he and Professor Robert Gale wrote: ‘The aim of CML therapy must be cure. But what exactly does this mean? Does it mean or require eradication of every CML cell in a person? We define cure as a situation where survival of persons with CML is identical to similar ageand gender-matched persons in the population without CML, associated with the absence of CMLrelated signs and symptoms’ [2] . The concept that a patient is considered cured when every leukemia cell has been eradicated is probably an oversimplification [3] . Furthermore, a DNA-based PCR might reveal BCR-ABL1-positive cells that are not detected by RNA-based, real-time, quantitative PCR, and ultrasensitive PCR techniques can discover a low level of BCRABL1 transcripts in the blood of normal individuals [3] . While remission means a temporary end to the medical signs and symptoms of a disease, cure means the absence of long-term relapse after treatment discontinuation. Received: September 29, 2015 Accepted: September 29, 2015 Published online: November 5, 2015
British journal of haematology, Jan 16, 2015
Carfilzomib has been established in previous years as a treatment for patients with relapsed and/... more Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort w...
Clinical Lymphoma Myeloma and Leukemia, 2015
S184 210 Very High Dose Cytarabine as Salvage Therapy for Relapsed or Refractory Acute Myeloid Le... more S184 210 Very High Dose Cytarabine as Salvage Therapy for Relapsed or Refractory Acute Myeloid Leukemia in the Setting of Intensified Anthracycline Induction and Post Stem-Cell Transplantation Gilad Itchaki, Ofir Wolach, Michal Bar-Natan, Moshe Yeshurun, Ron Ram, Corina Herscovici, Dan Douer, Martin Tallman, Ofer Shpilberg, Pia Raanani Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Leukemia & Lymphoma, 2015
A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamus... more A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamustine containing regimen between 2010-2014 was performed in order to determine the incidence and predictors for infection. The Kaplan Meier Model, employing log rank analysis, was used to assess time-to-infection. The Cox Proportional Hazards model was used to analyze multivariate effects of risk and 234 patients were included in the analysis. One hundred and nine (46.6%) developed at least one infection and 33.76% had severe infections. Seventy-six (41.5%) developed bacterial infection, nine (3.8%) fungal infection and 26 (11.5%) had viral infections. Factors significantly associated with time to infection on multivariable analysis were: bendamustine-combinations [hazard ratio (HR) = 0.589 (95% CI = 0.374-0.926), p = 0.022], Hb level [HR = 0.791 (95% CI = 0.716-0.875), p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001] and ischemic heart disease [HR = 1.828 (95% CI = 1.165-2.868), p = 0.009]. Infections were associated with a higher mortality and hospitalization rate.
British journal of cancer, 1995
Chemotherapy with the cytotoxic drug procarbazine (PCB) causes permanent infertility in most male... more Chemotherapy with the cytotoxic drug procarbazine (PCB) causes permanent infertility in most male patients. Since many patients treated with this cytotoxic drug are of reproductive age, it is important to develop a method to protect spermatogenesis and fertility. It has been hypothesised that 'spermatogenic arrest' by pharmacological intervention may render the testes less susceptible to the effects of chemotherapy. The present study investigated whether recovery of fertility in a male rat model could be achieved by suppression of spermatogenesis with high doses of clomiphene citrate (CC) prior to PCB administration. It was demonstrated that young male rats treated with a combination of CC and PCB partially recovered spermatogenesis and achieved almost normal fertility. In contrast, animals treated with PCB alone exhibited abnormal spermatogenesis and remained infertile.
Harefuah, 1991
Congenital afibrinogenemia is a rare hereditary disorder which has been described in only 150 fam... more Congenital afibrinogenemia is a rare hereditary disorder which has been described in only 150 families. The main clinical manifestations include spontaneous bleeding into the skin and into the gastrointestinal and genitourinary tracts. Skeletal manifestations are seldom reported. Laboratory findings include coagulation disorders corrected by administration of plasma, cryoprecipitate or fibrinogen. Development of antibodies to treatment with fibrinogen is rare. We report congenital afibrinogenemia in a 25-year-old man with rare complications which included skeletal manifestations such as bone cysts, and the development of antibodies to fibrinogen. Fibrinogen levels could only be maintained in the normal range by continuous infusion of cryoprecipitate, but not by bolus injections.
Acta Haematologica, 2014
Ofran and Rowe), chronic myeloid leukemia (by Pemmaraju and Cortes), acute promyelocytic leukemia... more Ofran and Rowe), chronic myeloid leukemia (by Pemmaraju and Cortes), acute promyelocytic leukemia (by Stein and Tallman), and stem cell transplantation for AYAs with hemato-oncological disorders (by Tewari et al.) were also included. With regard to nononcological disorders, Nowak-Göttl and Kenet reviewed the thrombophilias as well as the bleeding disorders in AYAs, and DeZern and Guinan concentrated on aplastic anemia while Yacobovich and Tamary focused on hemoglobinopathies. Regarding the supportive and comprehensive aspects of AYAs, Leader and Raanani studied adherence-related issues in AYAs with oncological as well as nononcological disorders. Dreyer and Schwartz-Attias covered the various nursing aspects, including quality of life perspectives, psychosocial aspects and spiritual existential views, while Foster and Stern as well as Kishtagari et al. focused on peer and romantic relationship experiences of AYA survivors of childhood cancer and on survivorship issues in AYAs, respectively. Finally, the multidisciplinary approach necessary for AYA patients is conveyed in the reviews on cardiotoxicity and fertility in this population covered by Lipshultz et al. and Shapira et al., respectively. And last but not least, Meeneghan and Wood discuss the current and future challenges in delivering quality care to AYA patients as well as the role of clinical trials with this respect. We believe that at the end of the day instead of being in the quandary of whom, how and where to treat these patients, they will be recognized as an entity in their own right. This issue, we hope, will contribute to the establishment of a new and more structured approach to the treatment of AYAs with hematological disorders. Adolescent and young adult (AYA) patients constitute a unique group that deserves special attention. There is a marked variability between the definitions of AYAs, ranging from 15–20 to 15–39 years. The distinct biology of the disease as well as other agerelated issues in AYA patients deserve unique psychological and medical attention and emphasize the necessity for a treatment approach taking into consideration their special needs. These include fertility considerations, survivorship issues, psychological support, adherence to treatment difficulties and other dilemmas and problems exclusive to this group of patients. AYA patients usually tolerate intensive treatments better than older adults do. If possible, they should be referred to special centers and should be encouraged to participate in clinical trials. In recent years, the focus on AYA patients in oncology and hemato-oncology has increased. Nevertheless, a distinct approach to these patients remains an unmet need. In this special issue, we hope to increase awareness for this group of patients as well as to emphasize the uniqueness of caring for their issues including special therapeutic challenges. The issue covers the wide spectrum of hematological disorders that are pertinent to AYA patients as well as supportive measures relevant to this group. Thus, Burke and Douer review the clinical and molecular characteristics of acute lymphoblastic leukemia in AYAs as well as the therapeutic approach, while Jachimowicz and Engert address these aspects in AYAs with Hodgkin’s lymphoma, and Wolach and Ram concentrate on non-Hodgkin’s lymphoma. Other hematological malignancies such as acute myeloid leukemia (reviewed by Published online: September 10, 2014
Acta Haematologica, 2014
Nonadherence to medical recommendations is a widespread problem well documented in a multitude of... more Nonadherence to medical recommendations is a widespread problem well documented in a multitude of clinical settings. Nonadherence may adversely affect clinical outcomes such as survival and quality of life and increase health-care-related costs. An understanding of the factors driving nonadherence is key to developing effective adherence-enhancing interventions (AEIs). There are ongoing attempts in contemporary adherence research to better define the various components of adherence, to find optimal measures of adherence and correlations with clinical outcomes, and to create a classification system for AEIs. Nonadherence is also widely prevalent among adolescents and young adults (AYAs) with chronic hematological diseases, affecting up to 50% of patients and increasing with age. Combined use of objective (i.e. electronic monitoring, EM) and subjective (i.e. self-report) measures of adherence may be the preferred approach to assess adherence. The unique physical, social and emotional aspects of the AYA life stage are closely related to intricate causes of nonadherence in AYAs such as problems in transition to adult care. Until proven otherwise, the empirical target in AYAs with hematological disorders should be perfect adherence. Multilevel AEIs, EM feedback and behavioral interventions are among the most effective types of AEIs. Despite the magnitude of the problem, only a handful of AEIs have been evaluated among AYAs with hematological disorders. Thus, this is a field with unmet needs warranting high-quality trials using standardized and well-specified assessment methods and interventions. This review discusses the prevalence, definition, causes and clinical implications of nonadherence among AYAs with hematological disorders, along with strategies to measure and improve adherence.
Acta Haematologica, 2011
In spite of decades of research in the field of allogeneic hematopoietic cell transplantation for... more In spite of decades of research in the field of allogeneic hematopoietic cell transplantation for the treatment of acute leukemia, controversies regarding the role of transplant still exist. These stem not only from contradictory results of different studies, but also from differences in the design and the strength of evidence of the various trials. Meta-analysis is considered the highest level
Reviews, 1996
Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs)... more Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs) are frequently administered during and after chemotherapy to reduce complications. However, their safety with regard to disease-related outcomes and survival in AML is unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the impact of CSFs on patient outcomes, including survival. To assess the safety/efficacy of CSFs with regard to disease-related outcomes and survival in patients with AML. We conducted a comprehensive search strategy. We identified relevant randomized clinical trials by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7), MEDLINE (January 1966 to July 2010), LILACS (up to December 2009), databases of ongoing trials and relevant conference proceedings. Randomized controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML. We excluded trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g. before and/or only for the duration of chemotherapy). Two review authors appraised the quality of trials and extracted data. For each trial, we expressed results as relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. We analyzed time-to-event outcomes as hazard ratios (HRs). The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival (HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates (RR 1.03; 95% CI 0.99 to 1.07), relapse rates (RR 0.97; 95% CI 0.89 to 1.05) and disease-free survival (HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias (RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections (RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm (RR 1.33; 95% CI 1.00 to 1.56). In summary, colony-stimulating factors should not be given routinely to acute myelogenous leukemia patients post-chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections.
Ash Annual Meeting Abstracts, Nov 16, 2004
ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), al... more ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), although about 40% of patients relapse or do not respond to initial treatment. Recently, the HD9 trial of the German Hodgkin’s Lymphoma Study Group has shown that escalated (esc) BEACOPP regimen can achieve better disease control than ABVD, but has a high incidence of acute and long-term toxicities including high occurrence of AML/MDS. In an attempt to decrease toxicity while preserving the potential benefit of upfront intensive therapy, we conducted a pilot study, which tested the feasibility, toxicity and efficacy of combined escBEACOPP-ABVD regimen as therapy for newly diagnosed patients with high risk (IPS≥3) stage III–IV HL. Patients initially received 2 cycles of escBEACOPP followed by reevaluation with CT and gallium or PET/CT-FDG scans. When complete response (CR) or partial response (PR) was achieved, patients continued to receive 4 cycles of ABVD, while those failing to achieve a response were withdrawn from the study. Since August 2001, 21 patients entered the study and at the time of present analysis four of them are still receiving therapy. Three (18%) of 17 patients, who completed chemotherapy, received consolidative radiotherapy. Median age at diagnosis was 26 years (range 18–56) and 11 (57%) were males. Stage IV and B symptoms were evidenced in 19 (90%) and 17 (81%), respectively, and 7 (33%) had bulky mediastinal mass. Histology included nodular sclerosis in 18 patients (86%), mixed cellularity in 2 (10%) and lymphocyte predominance in 1 (5%). Following the first 2 cycles of escBEACOPP the overall response rate (CR+PR) was 100%. At the end of all therapy 15 patients (88%) were in CR, one patient in PR and only a single patient had progressive disease. With a median follow-up of 20 months no patient relapsed or died. Toxicity included WHO grade III–IV granulocytopenia in 15 patients (88%) and grade III–IV infection in one patient. Hospitalization for intravenous antibiotics was necessary in 10 patients (59%). Almost all of these events occurred during the first two cycles of escBEACOPP, while acute toxicity during the ABVD phase was mild. In conclusion, the combined escBEACOPP-ABVD regimen is well tolerated and is associated with a high CR rate when used in advanced HL patients with high IPS scores. Further follow-up is obviously required in order to determine long-term survival and late complications of this regimen.
The Israel Medical Association Journal Imaj, Mar 1, 2012
Leukemia & lymphoma, Jan 16, 2016
Randomized clinical trials that compared chlorambucil to different regimens, for patients with ch... more Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of lo...
Proceedings of the National Academy of Sciences, 2015
Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tum... more Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow o...
Cardio-Oncology, 2015
Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myel... more Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs' safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.
Blood, Nov 15, 2013
Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-ri... more Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL). Protocol The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006]. Results As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant). Conclusions These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.
Ash Annual Meeting Abstracts, Nov 16, 2005
Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Alth... more Loss of fertility is a major concern in young women undergoing high dose chemotherapy (HDT). Although it is generally accepted that therapy of the myeloabelative range is related with a high rate of fertility loss, we observed during the last years eight spontaneous pregnancies with normal deliveries in young women after bone marrow transplantation. Seven patients (pt’s) were with lymphoma and MM and were conditioned with BEAM regimen (n=6) and melphalan 200mg/sm (n=1) prior to an autologous SCT, while one patient had a secondary AML and underwent BEAM primed autologous SCT and Busulfex/FA primed allogeneic BMT. The median age at transplant of this group was 28y and median time from transplant to pregnancy was 25 months. More than 100 women of 18–40y.o were transplanted in our center during this period; however, obviously the fertility rate cannot be calculated as it is related with additional parameters including survival, post transplant complications and mainly patient’s preferences. Naturally we observed during the same period many young patients with ovarian failure post transplant, as well as one successful pregnancy from a cryopreserved embryo. Methods. We Therefore initiated in October 2000 a fertility preservation program in which all women of 18 – 40y.o were offered a pretransplant IVF with embryo preservation, and/or ovarian tissue cryopreservation (OTC), according to their clinical status. 651 pt’s were transplanted in our center in the last 44 months, of which 81 were women of 18–41y.o that were all enrolled in this program. Results. Seven pt’s of this group (8.6%) underwent IVF. The major causes of denying IVF were the need to delay BMT for more than clinically accepted, prolonged preexisting ovarian failure, lack of a suitable partner and patient’s preference. Seventeen pt’s (21%) underwent OTC. The major causes of denying OTC were patient’s preference (mainly due to no evidence of success with this method) and thrombocytopenia/neutropenia. During this period: One patient of this group was fertilized with her cryopreserved embryos 32 months after transplant and is at her 16 week of pregnancy. One patient underwent a successful transplantation of her cryopreserved ovarian tissue 2.5 years after HDC while in a documented ovarian failure, and gave birth to a healthy baby on June 2005. The OTC of this patient was performed after cis-platinum containing salvage therapy for relapsing NHL, prior to BEAM primed SCT, and immediately after a failure of hormonal stimulation for IVF. One patient underwent a cryopreserved ovarian tissue transplantation on July 2005 Conclusions: 1. Spontanous pregnancy after HDT, mainly at the younger age, is not a rare phenomenon. 2. Most young patients prior to HDT are not eligible for IVF. 3. Pretransplant ovarian tissue cryopreservation is a feasible tool in this set-up. The first success with this method is promising.
Leukemia Research, 2015
Immunoparesis serves as a marker for elevated risk for progression in plasma cell proliferative d... more Immunoparesis serves as a marker for elevated risk for progression in plasma cell proliferative disorders. However, the impact of immunoparesis in AL amyloidosis has not been addressed. Immunoparesis was defined qualitatively as any decrease below the low reference levels of the uninvolved immunoglobulins and quantitatively, as the relative difference between the uninvolved immunoglobulins and the lower reference values. Forty-one newly diagnosed AL amyloidosis patients were included. Sixty-six percent of patients had a suppression of the uninvolved immunoglobulins. The median relative difference of the uninvolved immunoglobulins was 18% above the low reference levels [range (-71%)-210%]. Ninety percent of the patients were treated with novel agents-based regimens, mostly bortezomib-containing regimens. Nineteen percent of the patients did not attain response to first line treatment. Patients with relative difference of uninvolved immunoglobulins below -25% of the low reference levels were less likely to respond to first line treatment compared to patients with a relative difference of -25% and above [odds ratio for no response vs. partial response and better 30 [(95% CI 4.1-222.2), P=0.0004]. Patients who failed first line treatment were successfully salvaged with lenalidomide-based treatment. Immunoparesis, if assessed quantitatively, may serve as a predictor of response in AL amyloidosis patients treated with bortezomib-containing regimens.
Acta Haematologica, 2015
With the achievement of excellent results with tyrosine kinase inhibitors (TKIs), the next step w... more With the achievement of excellent results with tyrosine kinase inhibitors (TKIs), the next step was to conduct clinical trials aimed at stopping the treatment of patients on these drugs, namely, achieving a ‘cure’ or, alternatively, an ‘operational cure’. The pilot study on 12 CML patients was carried out by the pioneering group from Bordeaux led by Francois Mahon and it provided a proof of concept that imatinib discontinuation could be employed [4] . Since then, nearly 1,000 CML patients around the world have officially stopped using TKIs [5] . These studies gave answers to some of the questions raised regarding treatment discontinuation, such as the estimated rate of sustained molecular remission, factors predicting for prolonged molecular remission, the safety of discontinuing TKIs and the timing of molecular relapse after discontinuation. Yet, many issues remain open. These include the criteria for stopping TKIs – i.e. the depth and duration of molecular remission before discontinuation, the standardization of follow-up, i.e. the molecular threshold that triggers retreatment as well as the schedule and intensity of molecular follow-up after discontinuation. Last but not least, what place is there for treatment cessation outside of a clinical trial? Most studies have been conducted on patients who have achieved molecular remission in the range of a 4–4.5 First staged in 1895 in London, the play ‘The Importance of Being Earnest’, written by Oscar Wilde, challenged the social obligations of Victorian London society. One hundred and ten years later, also in London, the importance of being cured of chronic myeloid leukemia (CML) was challenged by the late Professor John Goldman, who coined the term ‘operational cure’ [1] . In one of his last publications, he and Professor Robert Gale wrote: ‘The aim of CML therapy must be cure. But what exactly does this mean? Does it mean or require eradication of every CML cell in a person? We define cure as a situation where survival of persons with CML is identical to similar ageand gender-matched persons in the population without CML, associated with the absence of CMLrelated signs and symptoms’ [2] . The concept that a patient is considered cured when every leukemia cell has been eradicated is probably an oversimplification [3] . Furthermore, a DNA-based PCR might reveal BCR-ABL1-positive cells that are not detected by RNA-based, real-time, quantitative PCR, and ultrasensitive PCR techniques can discover a low level of BCRABL1 transcripts in the blood of normal individuals [3] . While remission means a temporary end to the medical signs and symptoms of a disease, cure means the absence of long-term relapse after treatment discontinuation. Received: September 29, 2015 Accepted: September 29, 2015 Published online: November 5, 2015
British journal of haematology, Jan 16, 2015
Carfilzomib has been established in previous years as a treatment for patients with relapsed and/... more Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort w...
Clinical Lymphoma Myeloma and Leukemia, 2015
S184 210 Very High Dose Cytarabine as Salvage Therapy for Relapsed or Refractory Acute Myeloid Le... more S184 210 Very High Dose Cytarabine as Salvage Therapy for Relapsed or Refractory Acute Myeloid Leukemia in the Setting of Intensified Anthracycline Induction and Post Stem-Cell Transplantation Gilad Itchaki, Ofir Wolach, Michal Bar-Natan, Moshe Yeshurun, Ron Ram, Corina Herscovici, Dan Douer, Martin Tallman, Ofer Shpilberg, Pia Raanani Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Leukemia & Lymphoma, 2015
A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamus... more A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamustine containing regimen between 2010-2014 was performed in order to determine the incidence and predictors for infection. The Kaplan Meier Model, employing log rank analysis, was used to assess time-to-infection. The Cox Proportional Hazards model was used to analyze multivariate effects of risk and 234 patients were included in the analysis. One hundred and nine (46.6%) developed at least one infection and 33.76% had severe infections. Seventy-six (41.5%) developed bacterial infection, nine (3.8%) fungal infection and 26 (11.5%) had viral infections. Factors significantly associated with time to infection on multivariable analysis were: bendamustine-combinations [hazard ratio (HR) = 0.589 (95% CI = 0.374-0.926), p = 0.022], Hb level [HR = 0.791 (95% CI = 0.716-0.875), p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001] and ischemic heart disease [HR = 1.828 (95% CI = 1.165-2.868), p = 0.009]. Infections were associated with a higher mortality and hospitalization rate.
British journal of cancer, 1995
Chemotherapy with the cytotoxic drug procarbazine (PCB) causes permanent infertility in most male... more Chemotherapy with the cytotoxic drug procarbazine (PCB) causes permanent infertility in most male patients. Since many patients treated with this cytotoxic drug are of reproductive age, it is important to develop a method to protect spermatogenesis and fertility. It has been hypothesised that 'spermatogenic arrest' by pharmacological intervention may render the testes less susceptible to the effects of chemotherapy. The present study investigated whether recovery of fertility in a male rat model could be achieved by suppression of spermatogenesis with high doses of clomiphene citrate (CC) prior to PCB administration. It was demonstrated that young male rats treated with a combination of CC and PCB partially recovered spermatogenesis and achieved almost normal fertility. In contrast, animals treated with PCB alone exhibited abnormal spermatogenesis and remained infertile.
Harefuah, 1991
Congenital afibrinogenemia is a rare hereditary disorder which has been described in only 150 fam... more Congenital afibrinogenemia is a rare hereditary disorder which has been described in only 150 families. The main clinical manifestations include spontaneous bleeding into the skin and into the gastrointestinal and genitourinary tracts. Skeletal manifestations are seldom reported. Laboratory findings include coagulation disorders corrected by administration of plasma, cryoprecipitate or fibrinogen. Development of antibodies to treatment with fibrinogen is rare. We report congenital afibrinogenemia in a 25-year-old man with rare complications which included skeletal manifestations such as bone cysts, and the development of antibodies to fibrinogen. Fibrinogen levels could only be maintained in the normal range by continuous infusion of cryoprecipitate, but not by bolus injections.
Acta Haematologica, 2014
Ofran and Rowe), chronic myeloid leukemia (by Pemmaraju and Cortes), acute promyelocytic leukemia... more Ofran and Rowe), chronic myeloid leukemia (by Pemmaraju and Cortes), acute promyelocytic leukemia (by Stein and Tallman), and stem cell transplantation for AYAs with hemato-oncological disorders (by Tewari et al.) were also included. With regard to nononcological disorders, Nowak-Göttl and Kenet reviewed the thrombophilias as well as the bleeding disorders in AYAs, and DeZern and Guinan concentrated on aplastic anemia while Yacobovich and Tamary focused on hemoglobinopathies. Regarding the supportive and comprehensive aspects of AYAs, Leader and Raanani studied adherence-related issues in AYAs with oncological as well as nononcological disorders. Dreyer and Schwartz-Attias covered the various nursing aspects, including quality of life perspectives, psychosocial aspects and spiritual existential views, while Foster and Stern as well as Kishtagari et al. focused on peer and romantic relationship experiences of AYA survivors of childhood cancer and on survivorship issues in AYAs, respectively. Finally, the multidisciplinary approach necessary for AYA patients is conveyed in the reviews on cardiotoxicity and fertility in this population covered by Lipshultz et al. and Shapira et al., respectively. And last but not least, Meeneghan and Wood discuss the current and future challenges in delivering quality care to AYA patients as well as the role of clinical trials with this respect. We believe that at the end of the day instead of being in the quandary of whom, how and where to treat these patients, they will be recognized as an entity in their own right. This issue, we hope, will contribute to the establishment of a new and more structured approach to the treatment of AYAs with hematological disorders. Adolescent and young adult (AYA) patients constitute a unique group that deserves special attention. There is a marked variability between the definitions of AYAs, ranging from 15–20 to 15–39 years. The distinct biology of the disease as well as other agerelated issues in AYA patients deserve unique psychological and medical attention and emphasize the necessity for a treatment approach taking into consideration their special needs. These include fertility considerations, survivorship issues, psychological support, adherence to treatment difficulties and other dilemmas and problems exclusive to this group of patients. AYA patients usually tolerate intensive treatments better than older adults do. If possible, they should be referred to special centers and should be encouraged to participate in clinical trials. In recent years, the focus on AYA patients in oncology and hemato-oncology has increased. Nevertheless, a distinct approach to these patients remains an unmet need. In this special issue, we hope to increase awareness for this group of patients as well as to emphasize the uniqueness of caring for their issues including special therapeutic challenges. The issue covers the wide spectrum of hematological disorders that are pertinent to AYA patients as well as supportive measures relevant to this group. Thus, Burke and Douer review the clinical and molecular characteristics of acute lymphoblastic leukemia in AYAs as well as the therapeutic approach, while Jachimowicz and Engert address these aspects in AYAs with Hodgkin’s lymphoma, and Wolach and Ram concentrate on non-Hodgkin’s lymphoma. Other hematological malignancies such as acute myeloid leukemia (reviewed by Published online: September 10, 2014
Acta Haematologica, 2014
Nonadherence to medical recommendations is a widespread problem well documented in a multitude of... more Nonadherence to medical recommendations is a widespread problem well documented in a multitude of clinical settings. Nonadherence may adversely affect clinical outcomes such as survival and quality of life and increase health-care-related costs. An understanding of the factors driving nonadherence is key to developing effective adherence-enhancing interventions (AEIs). There are ongoing attempts in contemporary adherence research to better define the various components of adherence, to find optimal measures of adherence and correlations with clinical outcomes, and to create a classification system for AEIs. Nonadherence is also widely prevalent among adolescents and young adults (AYAs) with chronic hematological diseases, affecting up to 50% of patients and increasing with age. Combined use of objective (i.e. electronic monitoring, EM) and subjective (i.e. self-report) measures of adherence may be the preferred approach to assess adherence. The unique physical, social and emotional aspects of the AYA life stage are closely related to intricate causes of nonadherence in AYAs such as problems in transition to adult care. Until proven otherwise, the empirical target in AYAs with hematological disorders should be perfect adherence. Multilevel AEIs, EM feedback and behavioral interventions are among the most effective types of AEIs. Despite the magnitude of the problem, only a handful of AEIs have been evaluated among AYAs with hematological disorders. Thus, this is a field with unmet needs warranting high-quality trials using standardized and well-specified assessment methods and interventions. This review discusses the prevalence, definition, causes and clinical implications of nonadherence among AYAs with hematological disorders, along with strategies to measure and improve adherence.
Acta Haematologica, 2011
In spite of decades of research in the field of allogeneic hematopoietic cell transplantation for... more In spite of decades of research in the field of allogeneic hematopoietic cell transplantation for the treatment of acute leukemia, controversies regarding the role of transplant still exist. These stem not only from contradictory results of different studies, but also from differences in the design and the strength of evidence of the various trials. Meta-analysis is considered the highest level
Reviews, 1996
Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs)... more Acute myelogenous leukemia (AML) is a fatal bone marrow cancer. Colony-stimulating factors (CSFs) are frequently administered during and after chemotherapy to reduce complications. However, their safety with regard to disease-related outcomes and survival in AML is unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the impact of CSFs on patient outcomes, including survival. To assess the safety/efficacy of CSFs with regard to disease-related outcomes and survival in patients with AML. We conducted a comprehensive search strategy. We identified relevant randomized clinical trials by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 7), MEDLINE (January 1966 to July 2010), LILACS (up to December 2009), databases of ongoing trials and relevant conference proceedings. Randomized controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML. We excluded trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g. before and/or only for the duration of chemotherapy). Two review authors appraised the quality of trials and extracted data. For each trial, we expressed results as relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. We analyzed time-to-event outcomes as hazard ratios (HRs). The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival (HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates (RR 1.03; 95% CI 0.99 to 1.07), relapse rates (RR 0.97; 95% CI 0.89 to 1.05) and disease-free survival (HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias (RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections (RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm (RR 1.33; 95% CI 1.00 to 1.56). In summary, colony-stimulating factors should not be given routinely to acute myelogenous leukemia patients post-chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections.