Publications by authors named "Noam Benyamini"

30 Publications

  • Page 1 of 1

Characteristics and outcome of multiple myeloma patients presenting with anaemia only: A retrospective multi-centre study.

Leuk Res 2021 02 31;101:106498. Epub 2020 Dec 31.

Department of Hematology, Tel Aviv Sourasky Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.

Background: Multiple myeloma (MM) patients presenting with anaemia as their sole clinical manifestation are rare and not fully defined.

Methods: Retrospective multi-site study comparing the characteristics and outcome of MM patients with anaemia only with matched patients, presenting with multi-organ disease.

Results: Anaemia-only patients had a higher percentage of bone marrow monoclonal plasma cells group (median 60% [IQR 42-80%] vs. 37% [IQR 17-65%], respectively; p < 0.001), and a lower responsiveness to treatment (≥VGPR rates were 54% vs 74%, p = 0.049). Median survival in anaemia only patients was 65.9 ± 6.9 vs 83.4 ± 8.8 months in matched control patients (P = n.s).

Conclusions: MM patients presenting with anaemia only represents a unique, potentially less favorable population.
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http://dx.doi.org/10.1016/j.leukres.2020.106498DOI Listing
February 2021

Outcome of relapsed/refractory diffuse large B-cell lymphoma patients treated with polatuzumab vedotin-based therapy: real-life experience.

Leuk Lymphoma 2021 01 27;62(1):118-124. Epub 2020 Sep 27.

Hematology Division, Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The efficacy of polatuzumab vedotin in relapsed/refractory diffuse large B-cell lymphoma outside clinical study are undetermined. This retrospective study examined the efficacy and safety of polatuzumab vedotin administered in real life settings. Forty-seven patients, 31 with DLBCL and 16 with transformed lymphoma, treated with polatuzumab-based regimen in 14 Israeli centers between June 2018 and November 2019, were included. Median age was 66.1 years (60.4-78.8) and median number of prior lines was 3 (2-7). The overall response rate was 61% ( = 29), including 40% complete responses ( = 19) and 21% ( = 10) partial responses. The median overall survival and progression-free survival were 8.3 months and 5.6 months, respectively. An ECOG PS ≥2 predicted a decreased overall survival ( = 0.045). Primary refractory vs relapsed disease ( = 0.005) and transformed vs DLBCL ( = 0.039) were associated with shorter PFS ( = 0.027). Our data show that polatuzumab-based regimen is an effective and tolerable treatment in relapsed/refractory DLBCL.
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http://dx.doi.org/10.1080/10428194.2020.1824069DOI Listing
January 2021

The impact of anti-bacterial prophylaxis on the outcome of patients treated with venetoclax-based regimens for relapsed/refractory plasma cell dyscrasias: Real-life data.

Leuk Res 2020 10 30;97:106429. Epub 2020 Jul 30.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106429DOI Listing
October 2020

Bortezomib Maintenance Therapy as a Standard of Care Provides Favorable Outcomes in Newly Diagnosed Myeloma Patients: A Multisite Real-Life Study.

Clin Lymphoma Myeloma Leuk 2020 Nov 11;20(11):e850-e857. Epub 2020 Jun 11.

Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Lenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM.

Patients And Methods: A retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy.

Results: A total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P < .001) and OS (P < .001) among transplant-ineligible but not transplant-eligible patients.

Conclusion: Analysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease.
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http://dx.doi.org/10.1016/j.clml.2020.06.002DOI Listing
November 2020

Newly diagnosed myeloma patients with low-burden disease may benefit from tandem autologous stem cell transplantation: results of long-term follow-up.

Bone Marrow Transplant 2020 06 16;55(6):1200-1202. Epub 2019 Sep 16.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

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http://dx.doi.org/10.1038/s41409-019-0671-5DOI Listing
June 2020

Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.

Lancet Haematol 2019 Sep 18;6(9):e459-e469. Epub 2019 Jul 18.

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).

Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.

Findings: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.

Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
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http://dx.doi.org/10.1016/S2352-3026(19)30110-3DOI Listing
September 2019

Depletion of B cells rejuvenates the peripheral B-cell compartment but is insufficient to restore immune competence in aging.

Aging Cell 2019 08 6;18(4):e12959. Epub 2019 May 6.

Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B-cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B-cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B-cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals, were vaccinated against hepatitis B (HBV) after undergoing a detailed analysis for B-cell compartments. B-cell depletion in old mice resulted in rejuvenated B-cell population that was derived from de novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"-like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B-cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly depleted patients showed a "young"-like repertoire, population dynamics, and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and nondepleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B-cell compartment in aging, through B-cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population.
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http://dx.doi.org/10.1111/acel.12959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612643PMC
August 2019

Newly diagnosed multiple myeloma patients carrying monoallelic deletion of the whole locus of immunoglobulin heavy chain gene have a better prognosis compared to those with t(4;14) and t(14;16).

Genes Chromosomes Cancer 2019 08 6;58(8):516-520. Epub 2019 Feb 6.

Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Israel.

The current study evaluated the prognostic significance of the monoallelic deletion of the whole locus of the immunoglobulin heavy-chain (w_del(IGH)) gene compared to translocations t(4;14) and t(14;16) among newly diagnosed multiple myeloma (MM) patients. We retrospectively analyzed clinical (age, gender, and staging) and laboratory data at diagnosis and the overall survival (OS) of 255 newly diagnosed MM patients carrying w_del(IGH) or translocations t(4;14) or t(14;16). Bone marrow samples were examined by morphological and sequential interphase fluorescense in situ hybridization analyses. Among 255 patients, 117 (45.8%) had w_del(IGH), 99 (38.8%) had t(4;14), and 39 (15.3%) had t(14;16). Mean age was 61.6 ± 11.6 years. Groups did not differ significantly in age, gender, or lactate dehydrogenase levels. Patients in the w_del(IGH) group presented more frequently at International Staging System stage I than at stage II/III. Patients in the w_del(IGH) group had significantly fewer additional chromosomal aberrations (1.58) than the other two groups (2.3 and 2.13 in the del(IGH), t(14;16) and t(4;14) groups, respectively, P < 0.0001). Furthermore, the w_del(IGH) group had significantly longer estimated median OS (9.47 years) compared to those with translocations t(14;16) (3.02 years, P = 0.002) or t(4;14) (4.18 years, P = 0.001), respectively. These findings suggest a potential prognostic significance of monoallelic deletion of IGH among these patients. Additional studies are needed to better understand the nature and mechanism of this prognostic factor.
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http://dx.doi.org/10.1002/gcc.22738DOI Listing
August 2019

Identifying Tyrosine Kinase Inhibitor Nonadherence in Chronic Myeloid Leukemia: Subanalysis of TAKE-IT Pilot Study.

Clin Lymphoma Myeloma Leuk 2018 09 12;18(9):e351-e362. Epub 2018 Jun 12.

Institute of Nursing Science, Department Public Health, University of Basel, Switzerland; Academic Center of Nursing and Midwifery, Department Public Health and Primary Care, KU Leuven, Belgium.

Background: There are inconsistencies in reports on correlates for nonadherence (NA) to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). The diagnostic accuracy of subjective adherence measures using electronic monitoring (EM) as the reference standard is yet to be determined. This study aimed to evaluate correlates of TKI NA using EM and test the diagnostic accuracy of subjective adherence measures.

Patients And Methods: CML patients receiving a TKI for any duration were enrolled at 4 hematology institutes, and adherence was measured for 4 months. EM adherence was the reference adherence measure, expressed as the percentage of days with the drug taken as prescribed. Subjective adherence was measured using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) self-report and clinician-reported visual analog scale (VAS) at 2 time points. Baseline theory-derived correlates of NA were identified using single and multiple regression analysis. The diagnostic accuracy of BAASIS and clinician-reported VAS was tested against an exploratory EM NA cutoff of < 95%.

Results: The median EM adherence (n = 55) was 97.5% (range, 48-100%), while the 25th percentile was 92.1%. Lack of membership in a CML patient support group, living alone, and third-line treatment were associated with EM NA on multiple regression analysis. The BAASIS self-report (n = 94) had a sensitivity of 67% and a specificity of 71% for diagnosing NA, while clinician-reported VAS (n = 89) had a sensitivity of 78% and specificity of 42%.

Conclusion: A quarter of patients had potentially clinically meaningful NA. These NA correlates and the BAASIS provide a basis for identifying nonadherent patients who can be targeted by interventions.
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http://dx.doi.org/10.1016/j.clml.2018.06.007DOI Listing
September 2018

Severe cytomegalovirus enterocolitis developing following daratumumab exposure in three patients with multiple myeloma.

Eur J Haematol 2018 Aug 18. Epub 2018 Aug 18.

Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.

Objectives: The risk of cytomegalovirus (CMV) reactivation in multiple myeloma (MM) patients treated with bortezomib-based induction regimens is increased following autologous stem cell transplantation (ASCT). There is paucity of data regarding the risk of CMV infections in MM patients who did not receive bortezomib and ASCT.

Methods: We herein report three cases of heavily pretreated MM patients, receiving daratumumab-containing combination regimens, in whom ASCT had been performed long ago and who recently developed severe CMV-related gastrointestinal disease.

Results: All the three patients had a prolonged CMV disease course requiring a long-term antiviral treatment. All the patients suffered from CMV colitis. One patient had concurrent CMV duodenitis and another patient had a concurrent CMV retinitis.

Conclusion: Novel myeloma treatments prolong patient survival and more patients with profound immunosuppression following multiple lines of therapies are seen in clinical practice. These patients may present with opportunistic infections that were rare in the past. Our findings suggest a possible association between daratumumab therapy (in combination with other immunosuppressive therapies) and severe CMV gastrointestinal disease. A longer follow-up is needed to explore long-term side effects of novel agents like daratumumab in newly diagnosed as well as heavily pretreated MM patients.
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http://dx.doi.org/10.1111/ejh.13164DOI Listing
August 2018

Effect of Adherence-enhancing Interventions on Adherence to Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia (TAKE-IT): A Quasi-experimental Pre-Post Intervention Multicenter Pilot Study.

Clin Lymphoma Myeloma Leuk 2018 11 25;18(11):e449-e461. Epub 2018 Jun 25.

Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Nonadherence to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has been associated with inferior outcomes. Scarce evidence exists on the effectiveness of adherence-enhancing interventions. The present pilot study evaluated the feasibility and effectiveness of an intervention to improve TKI adherence in adult CML patients.

Patients And Methods: Using a quasi-experimental pre-post intervention design, we included a convenience sample of 58 CML patients (median age, 60.5 years; interquartile range, 19) receiving TKI treatment in 4 hematology institutes in Israel (median previous treatment duration, 34 months; interquartile range, 60). Of the 58 patients, 36 (62%) were receiving first-line treatment. TKI adherence was assessed using electronic monitoring for 7 months (4 months for the baseline assessment and for 3 months after the intervention) and defined as the percentage of days with dosing taken as prescribed. The multilevel intervention combined training of health care workers and multiple behavioral change techniques (eg, motivational interviewing, feedback on electronic monitoring printouts, behavioral change techniques tailored to reasons for nonadherence). The baseline and postintervention adherence were compared using generalized estimating equation models.

Results: The median baseline electronically monitored adherence (n = 55) was 97.5% (range, 48%-100%). The odds of taking the drug daily as prescribed were 58% greater after intervention (odds ratio, 1.58; 95% confidence interval [CI], 1.16-2.15). Adherence improved by only 1.5% overall (95% CI, 0.1%-2.8%) but by 8.5% (i.e. from 71.2% average adherence before intervention, to 79.6% after; P = .04) in a subgroup of 10 nonadherent patients (baseline adherence < 90%).

Conclusion: TKI adherence improved with our pilot intervention, mainly in patients with suboptimal baseline adherence.
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http://dx.doi.org/10.1016/j.clml.2018.06.026DOI Listing
November 2018

Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study.

Ann Intern Med 2018 04 20;168(7):461-470. Epub 2018 Feb 20.

University of Adelaide, Adelaide, South Australia, Australia (T.P.H.).

Background: Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML).

Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy.

Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905).

Setting: 63 centers in 18 countries.

Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR.

Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment.

Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point).

Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation.

Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment.

Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib.

Primary Funding Source: Novartis Pharmaceuticals Corporation.
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http://dx.doi.org/10.7326/M17-1094DOI Listing
April 2018

[HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE PERSPECTIVE OF TIME AND UP TO THE 2000 TRANSPLANT AT THE RAMBAM HEALTH CARE CAMPUS].

Harefuah 2017 Sep;156(9):589-594

Rambam Health Care Campus.

Introduction: Stem cell transplantation is indicated in hematological malignancies as well as some solid tumors and congenital abnormalities. Autologous transplantation allows the administration of high dose chemotherapy without prolonged bone marrow aplasia. Allogeneic transplantation allows us to give the patient a new immune system that can locate and destroy remaining tumor cells. First attempts in patients began in 1939. Improved outcomes occurred after discovering the human leukocyte antigen system which allowed for matching the donor to the patient. Immunosuppression therapy to prevent graft versus host disease also improved the outcomes. Since the 1970's, more and more centers in North America and Europe opened stem cell transplantation programs. Today it is performed worldwide and on December 2012, the one million milestone transplant worldwide was achieved. The bone marrow transplantation program started at Rambam Health Care campus on September 1995. Since then 2000 transplantations were performed at Rambam. A third of these procedures were allogeneic and two thirds were autologous. In the last decade patient survival has improved significantly due to better supportive care and the use of reduced intensity conditioning relying on the graft versus tumor effect (GVT). New ways to reduce graft versus host disease (GVHD), while improving GVT effect are based on manipulating T cells in the graft and on genetically engineered T cell with enhanced antitumor cytotoxicity. In the future, allogeneic transplantation will become more complex, more individualized and more efficient.
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September 2017

Acute myeloid leukemia during pregnancy: a systematic review and meta-analysis.

Leuk Lymphoma 2018 03 13;59(3):610-616. Epub 2017 Jul 13.

e Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.

Data regarding clinical characteristics, therapy, maternal and fetal outcomes of pregnancy-associated acute myeloid leukemia (PA-AML) are limited. This study (including 138 cases published between 1955 and 2013) provides comprehensive assessment of these clinical parameters and may serve as a platform for developing management recommendations. Most patients (58%) received anthracycline-cytarabine-based regimens (ACBRs), which were associated with significantly increased complete remission (CR: 91%). Yet, the maternal overall survival (OS: ∼30%) was relatively low, probably reflecting reduced application of risk-adapted consolidation and allogeneic stem cell transplantation (allo-SCT). Fetal exposure to ACBRs resulted in a live birth rate of 87%, with complications (16%) diagnosed only in chemotherapy-subjected neonates. This study demonstrates safety and efficacy of ACBRs during pregnancy. Therapy and delivery schedule should allow early referral of high-risk patients to allo-SCT. Generation of a pool of high-quality data on PA-AML could contribute to providing evidence-based therapy and lead to improved maternal and fetal survival.
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http://dx.doi.org/10.1080/10428194.2017.1347651DOI Listing
March 2018

Integration of CT-Based Measurements into Surveillance PET/CT in Patients with Diffuse Large B Cell Lymphoma.

Isr Med Assoc J 2016 Jul;18(7):411-417

Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: Despite the lack of clinical studies supporting the use of routine surveillance FDG-positron emission tomography (PET) in patients with diffuse large B cell lymphoma (DLBCL) who achieved remission, many centers still use this strategy, especially in high risk patients. Surveillance FDG-PET computed tomography (CT) is associated with a high false positive (FP) rate in DLBCL patients.

Objectives: To investigate whether use of specific CT measurements could improve the positive predictive value (PPV) of surveillance FDG-PET/CT.

Methods: This retrospective study included DLBCL patients treated with CHOP or R-CHOP who achieved complete remission and had at least one positive surveillance PET. CT-derived features of PET-positive sites, including long and short diameters and presence of calcification and fatty hilum within lymph nodes, were assessed. Relapse was confirmed by biopsy or consecutive imaging. The FP rate and PPV of surveillance PET evaluated with/without CT-derived measurements were compared.

Results: Seventy surveillance FDG-PET/CT scans performed in 53 patients were interpreted as positive for relapse. Of these studies 25 (36%) were defined as true-positive (TP) and 45 (64%) as FP. Multivariate analysis found long or short axis measuring ≥ 1.5 and ≥ 1.0 cm, respectively, in PET-positive sites, International Prognostic Index (IPI) ≥ 2, lack of prior rituximab therapy and FDG uptake in a previously involved site, to be independent predictors of true positive surveillance PET (odds ratio 5.4, 6.89, 6.6, 4.9, P < 0.05 for all).

Conclusions: PPV of surveillance PET/CT may be improved by its use in selected high risk DLBCL patients and combined assessment of PET and CT findings.
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July 2016

Comparison of engraftment following different stem cell mobilization modalities in patients with multiple myeloma treated with a uniform induction regimen containing bortezomib, cyclophosphamide and dexamethasone.

Ann Hematol 2017 Mar 24;96(3):461-467. Epub 2016 Dec 24.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8, Ha'Aliya Street, 31096, Haifa, Israel.

Bortezomib-based induction followed by autologous stem cell transplantation is a common treatment for multiple myeloma (MM). Stem cell (SC) mobilization with granulocyte-colony stimulating factor (G-CSF) alone has become an alternative to G-CSF combined with chemotherapeutic agents. This study aimed to compare the efficacy of the two mobilization modalities following induction with a uniform regimen containing bortezomib, cyclophosphamide and dexamethasone (VCD). We retrospectively evaluated results of SC mobilization using either G-CSF alone or combined with high-dose cyclophosphamide (HD-CY) in MM patients after VCD induction. The primary endpoints of the study were engraftment and mobilization-associated toxicity. Parameters of stem cell collection, transplantation and engraftment were assessed. Data of 92 patients were analyzed [56 (61%) mobilized with HD-CY + G-CSF and 36 (39%) with G-CSF only]. HD-CY + G-CSF provided a higher number of CD34 + cells (15.9 vs 8.1 × 10/kg, p = 0.001) with fewer apheresis sessions. However, while no adverse events were observed in patients receiving G-CSF alone, nine patients (16%) receiving HD-CY + G-CSF developed neutropenic fever requiring hospitalization. Although a greater number of cells was transplanted following mobilization with HD-CY + G-CSF, neutrophil and platelet engraftment and duration of transplant-related hospitalization were similar in both cohorts. G-CSF alone provided a sufficient SC amount, without exposing patients to additional toxicity. While HD-CY + G-CSF resulted in a superior SC yield in MM patients induced with VCD, this advantage should be balanced against adverse effects of this mobilization regimen.
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http://dx.doi.org/10.1007/s00277-016-2897-2DOI Listing
March 2017

Progressive refractory light chain amyloidosis and multiple myeloma patients are responsive to the addition of clarithromycin to IMiD based therapy.

Am J Hematol 2017 02 21;92(2):131-135. Epub 2016 Nov 21.

Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24596DOI Listing
February 2017

Serum free immunoglobulin light chain fingerprint identifies a subset of newly diagnosed multiple myeloma patients with worse outcome.

Hematol Oncol 2017 Dec 19;35(4):734-740. Epub 2016 Sep 19.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.

Multiple myeloma (MM) is a multi-subclonal malignancy with relatively high heterogeneity. Patients who initially presented with both monoclonal-protein (MP) and free light chain (FLC) secretion but then relapsed with a light chain escape pattern have been shown to reflect disease clonal evolution and to bare a worse prognosis. We hypothesized that a discordant MP/FLC pattern at diagnosis may reflect a similar clonal evolution that had occurred prior to diagnosis of active myeloma, conferring a worse outcome. We analyzed 255 consecutive newly diagnosed MM patients who received first line bortezomib-based therapy between 2007 and 2014, hypothesizing that their MP/FLC fingerprint at diagnosis reflects clonal heterogeneity and, therefore, affects outcome. An involved FLC level ≥ 700 mg/L and MP ≥ 2.5 g/L were used as cutoffs for low vs high FLC and MP levels, respectively. Patients were divided into 4 subgroups according to their involved FLC and MP blood levels at diagnosis: HiLC and HiMP for patients with either a predominant FLC or a predominant MP, respectively, and HiLC-MP and LoLC-MP when both FLC and MP were increased or decreased, respectively. There were 68 (27%) patients with HiLC, which presented more often with International Staging System-3 stage (P < .0001). Multivariate analysis showed that HiLC was associated with a 5.1-fold risk for mortality in a multivariate model (95% confidence interval [CI], 1.34-19.68). Both HiLC and HiLC-MP phenotypes were associated with shorter progression-free survival (hazard ratio of 2.66 [95% CI, 1.33-5.32] and 2.82 [95% CI, 1.37-5.83], respectively), independently of other prognostic factors, including the use of autograft. Thus, we identified an LC predominant secretory fingerprint (HiLC phenotype) at diagnosis as a potential independent risk factor that may affect disease control and survival in newly diagnosed MM patients treated with bortezomib-based induction therapy; this may represent increased subclonal heterogeneity.
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http://dx.doi.org/10.1002/hon.2336DOI Listing
December 2017

Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable?

Genes Chromosomes Cancer 2016 09 24;55(9):710-8. Epub 2016 Jun 24.

Division of Hematology and Bone Marrow Transplantation, and the Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel.

The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32). According to several studies, this translocation represents a unique subset of patients with relatively favorable outcomes. Using combined analyses of morphology and fluorescence in situ hybridization (I-FISH), we examined the co-occurrence rates of t(11;14) with seven chromosomal aberrations (CAs), del(13q), del(17p), del(1p), gain(1q), multiple gains(1q), del(16q), and del(IGH), and assessed the effect of the different combinations on patient outcomes, with overall survival (OS) as the main outcome measure. Bone marrow samples and clinical data from 212 patients with MM with t(11;14) were analyzed. At least two additional CAs were found in 35% (75/205) of patients and a strong correlation between specific CAs. The occurrence of three CAs [multiple gains of (1q) (HR = 6.94, P = 0.001), del(1p) (HR = 4.47, P = 0.008), and del(IGH) (HR = 2.38, P = 0.002)] exerted a profoundly deleterious effect on median OS when compared with patients with t(11;14) only. Del(17p) and del(13q) have also exerted a deleterious effect albeit to a lesser extent (HR = 2.05, P = 0.07 and HR = 1.81, P = 0.03, respectively). When compared with t(11;14) alone, the addition of certain CAs lead to worse outcomes. These findings may have important clinical and biological implications. Patients with coexisting adverse lesions and t(11;14) may be considered at high risk and managed accordingly. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22372DOI Listing
September 2016

Primary failure of bortezomib in newly diagnosed multiple myeloma--understanding the magnitude, predictors, and significance.

Leuk Lymphoma 2016 4;57(6):1382-8. Epub 2016 Jan 4.

c Department of Clinical Therapeutics , National & Kapodistrian University of Athens School of Medicine , Athens , Greece.

Botezomib-based induction is highly effective for the treatment of newly diagnosed multiple myeloma (NDMM). We investigated the outcomes of NDMM patients who failed to respond to bortezomib-based induction in a 'real-life' clinical setting. In a cohort of 295 consecutive NDMM patients in 3 medical centers, 74 (25%) failed to achieve at least partial response after 4 induction cycles, and were classified as non-responsive. Compared to induction responders, they were older, more frequently anemic, had a higher incidence of del17p and ISS-3, and a worse performance status. In multivariable analysis, bortezomib-based induction failure occurred in 25% of patients and was the strongest independent factor predicting mortality with a 5-fold hazard ratio (95% CI 1.44-8.68). Three-year overall survival in responsive vs. non-responsive patients were 76% vs. 53%, respectively (p < 0.0001). Survival from time of salvage second-line treatment was significantly shorter among induction non-responders vs. responders (25 months vs. not-reached, p = 0.024).
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http://dx.doi.org/10.3109/10428194.2015.1121258DOI Listing
January 2017

Dendritic cell cancer vaccines: from the bench to the bedside.

Rambam Maimonides Med J 2014 Oct 29;5(4):e0024. Epub 2014 Oct 29.

Hematological Malignancies and Bone Marrow Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both "passive" (e.g. strategies relying on the administration of specific T cells) and "active" vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target "immunosuppressive checkpoints" (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination.
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http://dx.doi.org/10.5041/RMMJ.10158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222413PMC
October 2014

Development of multifocal leukoencephalopathy in patients undergoing allogeneic stem cell transplantation-can preemptive detection of John Cunningham virus be useful?

Int J Infect Dis 2014 Sep 16;26:107-9. Epub 2014 Jul 16.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8, Ha'Aliya Street, Haifa 31096, Israel.

Therapeutic options for progressive multifocal leukoencephalopathy (PML) caused by reactivation of John Cunningham virus (JCV) are limited and inefficient in preventing neurological progression and death. The current study investigated the course of JCV reactivation resulting in PML in patients undergoing allogeneic stem cell transplantation (allo-SCT) and assessed the feasibility and potential significance of preemptive JCV detection in peripheral blood, enabling early cessation of immunosuppressive therapy and immune restoration. Two allografted patients were diagnosed with PML at 188 and 808 days post-allo-SCT. Stored DNA samples of both patients, originally obtained for quantitative cytomegalovirus PCR analysis since transplantation, were evaluated for JCV. JCV reactivation in peripheral blood was found to precede the appearance of neurological symptoms by 126 and 105 days. JCV blood levels were found to be highly correlated with the steroid dosage administered for treating graft-versus-host disease (GVHD). In one patient, the cessation of immunosuppression, including steroids, led to the disappearance of JCV in peripheral blood, with a remarkable improvement in neurological symptoms. In conclusion, the current study suggests the feasibility of early detection of JCV reactivation in blood. Immune restoration at that point may prevent PML development; however prospective studies are warranted to elucidate these issues.
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http://dx.doi.org/10.1016/j.ijid.2014.03.1381DOI Listing
September 2014

Is there a role for therapy response assessment with 2-[fluorine-18] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in mantle cell lymphoma?

Leuk Lymphoma 2014 Nov 7;55(11):2484-9. Epub 2014 Mar 7.

Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center , Tel-Hashomer , Israel.

2-[Fluorine-18] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) scanning is used for response assessment in mantle cell lymphoma (MCL). However, its ability to predict outcome is debatable. We retrospectively evaluated the prognostic impact of interim and post therapy FDG-PET/CT scan on outcome of 58 consecutive MCL patients. Scans performed at diagnosis, mid-therapy, post-chemotherapy and post-transplant were reviewed and outcome analyzed. Median age was 59; MCL International Prognostic Index (MIPI) was low in 45%, intermediate in 41% and high in 14%. Thirty-four patients (58%) received R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) or R-CHOP-like chemotherapy, 24 (42%) underwent upfront autologous stem-cell transplant (ASCT). Three-year overall (OS) and progression-free-survival (PFS) were 81% and 45%, respectively. No differences in OS or PFS between PET-positive and PET-negative groups both for interim and post-therapy scans were observed. We conclude that in patients treated with R-CHOP, using the International-Harmonization-Project criteria for FDG-PET/CT interpretation, there is no role for interim or post-therapy PET.
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http://dx.doi.org/10.3109/10428194.2014.882506DOI Listing
November 2014

Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial.

Am J Infect Control 2013 Dec;41(12):1167-72

Infectious Diseases Unit, Rambam Health Care Campus, Haifa, Israel; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address:

Background: Carbapenem-resistant Enterobacteriaceae (CRE) are emerging. In attempt to eradicate CRE colonization, we conducted a semirandomized, prospective, controlled trial using oral nonabsorbable antibiotics.

Methods: Consecutive hospitalized CRE carriers were studied. Patients whose rectal isolates were gentamicin sensitive but colistin resistant were treated with gentamicin. Patients whose isolates were colistin sensitive but gentamicin resistant were treated with colistin. Patients whose isolates were sensitive to both drugs were randomized to 3 groups of oral antibiotic treatment: gentamicin, colistin, or both. Patients whose isolates were resistant to both drugs, and those who did not consent, were followed for spontaneous eradication.

Results: One hundred fifty-two patients were included; 102 were followed for spontaneous eradication for a median duration of 140 days (controls), and 50 received 1 of the 3 drug regimens: gentamicin, 26; colistin, 16; both drugs, 8, followed for a median duration of 33 days. Eradication rates in the 3 treatment groups were 42%, 50%, and 37.5%, respectively, each significantly higher than the 7% spontaneous eradication rate in the control group (P < .001, P < .001, and P = .004, respectively) with no difference between the regimens. No significant adverse effects were observed.

Conclusion: Oral antibiotic treatment with nonabsorbable drugs to which CRE is susceptible appears to be an effective and safe for eradication of CRE colonization and, thereby, may reduce patient-to-patient transmission and incidence of clinical infection with this difficult-to-treat organism.
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http://dx.doi.org/10.1016/j.ajic.2013.04.018DOI Listing
December 2013

Is there a role for allogeneic transplantation in chronic myeloid leukemia?

Expert Rev Hematol 2013 Dec;6(6):759-65

Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa 31096, Israel.

Allogeneic hemopoietic cell transplantation has moved away from being the standard of care for patients with chronic myeloid leukemia (CML). Its role is currently limited to an unsatisfactory response to therapy with tyrosine kinase inhibitors as well as advanced stages of the disease. The advent of tyrosine kinase inhibitors has been one of the most remarkable advances in any form of cancer. Never-the-less, as a definitive procedure, allogeneic transplantation remains the only curative modality and its use in carefully selected patients, who have an inadequate response, has been increasingly recognized. It remains a standard of care for patients who present with blast crisis CML and is often used also in accelerated phase. The future for patients with CML has become so much brighter over the past decade but new issues and considerations continually emerge.
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http://dx.doi.org/10.1586/17474086.2013.849571DOI Listing
December 2013

Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era.

Haematologica 2014 Jan 9;99(1):125-30. Epub 2013 Aug 9.

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.
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http://dx.doi.org/10.3324/haematol.2013.088161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007925PMC
January 2014

Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review.

Lancet Oncol 2013 Jun;14(7):e275-82

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

Data for pregnancy-associated non-Hodgkin lymphoma are limited to case reports, making it difficult to define this disorder. We did a systematic search for articles published between 1967 and 2011 with the aim to determine the characteristics, management, and outcome of pregnancy-associated non-Hodgkin lymphoma. We identified 121 patients from 74 papers. Most patients with stage information available presented with stage IV disease (75%, 82 of 108 patients). Patients were classified into three clinical groups; those with indolent lymphomas accounted for 5% (five of 108), aggressive lymphomas (diffuse large B-cell lymphoma and T-cell lymphomas) made up 48% of patients (52 of 108), and highly aggressive lymphomas (Burkitt's lymphoma, immunoblastic lymphoma, and unspecified highly aggressive lymphomas) accounted for 47% of patients (51 of 108). Reproductive organ involvement (breast, ovary, uterus, placenta) was reported in 49% of 110 patients with information available on extranodal involvement, and prevailed in endemic Burkitt's lymphoma (100%, 19 of 19), followed by non-endemic Burkitt lymphoma (70%, 14 of 20), immunoblastic lymphoma (67%, two of three), peripheral T-cell lymphoma (46%, six of 13), and indolent (40%, two of five) and diffuse large cell lymphoma (23%, nine of 40). Most patients received antepartum (45%, 55 of 121) or postpartum therapy (45%, 54 of 121), resulting in 6-month survival of 53% for mothers and a livebirth rate of 83%. Pregnancy-associated non-Hodgkin lymphoma has unique clinical characteristics with frequent reproductive organ involvement. Collaborative prospective studies are needed to further characterise pathophysiological and clinical aspects of this complication.
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http://dx.doi.org/10.1016/S1470-2045(12)70589-2DOI Listing
June 2013

New rising infection: human herpesvirus 6 is frequent in myeloma patients undergoing autologous stem cell transplantation after induction therapy with bortezomib.

Bone Marrow Res 2012 29;2012:409765. Epub 2012 Nov 29.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel.

Herpesvirus 6 (HHV-6) infection is a common complication during immunosuppression. Its significance for multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) after treatment with novel agents affecting immune system remains undetermined. Data on 62 consecutive MM patients receiving bortezomib-dexamethasone (VD) (n = 41; 66%) or thalidomide-dexamethasone (TD) (n = 21, 34%) induction, together with melphalan 200 mg/m(2) autograft between 01.2005 and 09.2010, were reviewed. HHV-6 reactivation was diagnosed in patients experiencing postengraftment unexplained fever (PEUF) in the presence of any level of HHHV-6 DNA in blood. There were no statistically significant differences in patient characteristics between the groups, excluding dexamethasone dosage, which was significantly higher in patients receiving TD. Eight patients in TD and 18 in VD cohorts underwent viral screening for PEUF. HHV-6 reactivation was diagnosed in 10 patients of the entire series (16%), accounting for 35% of those screened; its incidence was 19.5% (n = 8) in the VD group versus 9.5% (n = 2) in the TD group. All patients recovered without sequelae. In conclusion, HHV-6 reactivation is relatively common after ASCT, accounting for at least a third of PEUF episodes. Further studies are warranted to investigate whether bortezomib has an impact on HHV-6 reactivation development.
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http://dx.doi.org/10.1155/2012/409765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517825PMC
December 2012