Nadav Sarid

Absolute monocyte count trichotomizes chronic lymphocytic leukemia into high risk patients with immune dysregulation, disease progression and poor survival

Peripheral absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral AMC in 80 treatment naive patients with CLL. Measurement of AMC was based on direct morphological enumeration, due to our findings that complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was within normal limits, however the AMC range exceeded the values of healthy individuals. The AMC trichotomized patients into 3 distinct sub-groups with different characteristics and outcomes. High AMC patients were younger and had higher absolute lymphocytes count, while patients with low AMC had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroups, whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes.

The Value of PET/CT in Detecting Bone Marrow Involvement in Patients With Follicular Lymphoma.

AbstractFollicular lymphoma (FL) is the 2nd most common type of lymphoma diagnosed in the Western World. Bone marrow (BM) involvement is an adverse prognostic factor in FL, routinely assessed by an arbitrary biopsy of the iliac crest. This study was aimed to investigate the role of positron emission tomography/computed tomography (PET/CT) in identifying BM involvement by FL.In this retrospective, single-center study we reviewed the records of consecutive patients with FL at diagnosis or relapse who underwent staging/restaging workup visual assessment of BM uptake was categorized as either normal, diffusely increased, or focally increased. Quantitative BM fluorine-18-fluro-deoxyglucose (FDG) uptake was measured using mean standardized uptake value (BM-SUVmean). The diagnosis of BM involvement was based on either BM histological findings or disappearance of increased uptake at end-treatment PET/CT in patients who responded to treatment.Sixty eight cases with FL were included. Sixteen (23.5%) had BM involvement, 13 (19.1%) had a biopsy proven involvement, and 3 (4.4%) had a negative BM biopsy, but increased medullary uptake that normalized post-treatment. BM FDG uptake in these patients was diffuse in 8 (50%) and focal in 8 (50%). Focal increased uptake was indicative of BM involvement; however, diffuse uptake was associated with 17 false positive cases (32.7%). Overall, visual assessment of BM involvement had a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 48.5%. On a quantitative assessment, BM-SUVmean was significantly higher in patients with BM involvement (SUVmean of 3.7 [1.7–6] vs 1.4 [0.4–2.65], P < 0.001). On receiver operator curve (ROC) analysis, BM-SUVmean > 2.7 had a PPV of 100% for BM involvement (sensitivity of 68%), while BM-SUVmean < 1.7 had an NPV of 100% (specificity of 73%).Visual assessment of PET/CT is appropriate for ruling out BM involvement by FL. Although focal increased uptake indicates marrow involvement, diffuse uptake is nonspecific. SUV measurement improves PET/CT diagnostic accuracy, identifying additional 19% of patients with BM involvement that would have been otherwise missed.

Reduced-dose ICE chemotherapy ± rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma

Abstract The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.

Predictive value of TP53 fluorescence in situ hybridization in cytogenetic subgroups of acute myeloid leukemia

Acute myeloid leukemia (AML) with a complex karyotype (CK) has frequent alterations in TP53 and a very poor prognosis. We examined whether a prompt and simple fluorescence in situ hybridization (FISH) analysis for 17p13 deletion at diagnosis has a predictive value for response to therapy and overall survival in subgroups of AML. In 15 patients with a normal karyotype the TP53 FISH analysis was normal, whereas in 16 patients with CK 75% had only one copy of the TP53 allele. The deletion was also detected in 33% of six patients with monosomy or partial monosomy of chromosome 5, 7, 9, or 12. This loss of TP53 correlated significantly with a poor response to chemotherapy, and the median survival time of these patients was shorter. TP53 FISH analysis carried out at diagnosis has a predictive value with respect to chemotherapy response and can therefore facilitate a rapid decision on treatment strategies.

High response rate for treatment with gemtuzumab ozogamicin and cytarabine in elderly patients with acute myeloid leukemia and favorable and intermediate-I cytogenetic risk.

UNLABELLED Recent studies have reevaluated whether gemtuzumab ozogamicin (GO) improves the outcome of acute myeloid leukemia (AML) in elderly patients. Over 5 years, we treated 16 elderly patients with AML with GO and cytarabine. A high response rate, prolonged survival, and low toxicity were observed in the favorable and intermediate-I genetic groups of AML. Our study raises the issue about the optimal protocol for these patients. BACKGROUND The benefit of gemtuzumab ozogamicin (GO) in combination with chemotherapy as frontline therapy in patients with acute myeloid leukemia (AML) is still debated. PATIENTS AND METHODS We evaluated the safety and efficacy of low-dose GO with cytarabine in elderly patients with newly diagnosed AML. Over the past 5 years, we have treated 16 elderly patients with AML (64-82 years) with GO (3 mg/m(2)) followed by continuous infusion of cytarabine (100 mg/m(2)) for 7 days. RESULTS Complete remission (CR) was achieved in 68.8% of patients; however, this was true only in patients in the favorable or intermediate-I cytogenetic risk groups. Of the 12 patients with AML in the favorable and intermediate-I genetic groups, 11 (91.7%) achieved CR. By comparison, of all 4 patients in the intermediate-II or adverse genetic groups, none of the patients achieved CR (P = .003). The median disease-free survival and overall survival (OS) was 10.9 and 18.8 months, respectively, for patients who achieved CR. The estimated median survival was 15 months in the favorable and intermediate-I cytogenetic groups and only 4.4 months in the intermediate-II and unfavorable risk groups (P = .008). The toxicity profile was also manageable in patients with AML who were mainly older than 70 years with good performance status (PS). The 8-week mortality rate was 6.25%, which is relatively low in this high-risk group of patients. These data are in line with results from 2 randomized trials suggesting that the addition of low-dose GO should be further investigated to reevaluate its role in selected elderly patients with AML and raises the issue of the optimal protocol.

Treatment and prognosis of stage I follicular lymphoma in the modern era – does PET matter?

Abstract Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography–computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60–80% and 80–93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of “genuine” stage I disease.

Acute myeloid leukemia with 11q23/MLL rearrangement after 'FCR' regimen for chronic lymphocytic leukemia.

To the editor: The regimen of fludarabine, cyclophosphamide, and rituximab (FCR) is the standard frontline therapy for physically fit patients with chronic lymphocytic leukemia (CLL) (1). There is growing concern about the leukemogenic potential of fludarabine combination chemotharapy for the treatment of lymphoproliferative disorders (2). Acute myeloid leukemia (AML) with 11q23 abnormalities involving the MLL gene comprises one category of recurring genetic abnormalities in the WHO classification (3). This AML subtype typically evolves within 1–3 years after topoisomerase II inhibitors-containing chemotherapy (4). We report the first case of therapy-related AML with 11q/MLL rearrangement in a CLL patient treated upfront with FCR, a regimen without topoisomerase II inhibitors. A 50 years old men presented with weight loss, generalized lymphadenopathy, and lymphocytosis. A diagnosis of CLL (Rai stage 2) was made based on typical morphology and immunophenotyping. Risk group stratification defined the disease as ZAP70/CD38 positive with unmutated VH 3-74. Fluorescence in situ hybridization (FISH) revealed no chromosomal abnormalities, and b-2-microglobulin was 3.14 mg/mL. He received six cycles of FCR (fludarabine 25 mg/m, cyclophosphamide 250 mg/m for 3 days/cycle, with rituximab at 375 mg/m on first cycle and 500 mg/m, cycles 2–6). Complete clinical and immunophenotypic response was achieved. Nine months later, he developed dyspnea and epistaxis, with extreme leukocytosis (400 9 10/L). Morphology and immunophenotyping were consistent with acute monoblastic leukemia, without any CLL. G-banded karyotype showed t(9;11) (p22;q23), confirmed by FISH (Fig. 1). To verify whether the 11q23/MLL rearrangement indeed evolved after therapy for CLL, we analyzed the patient’s blood samples before FCR treatment and at the diagnosis of AML. Quantitative PCR confirmed that (9;11)(p22;q23) was detectable only at the time of AML and not before initiating the FCR therapy (Fig. 2). Symptoms related to leukostasis, spontaneous tumor lysis syndrome, and acute renal failure necessitated leukapheresis. He then failed therapy with ‘7 + 3’ induction regimen (cytarabine and idarubicin) and subsequent salvage chemotherapy. While undergoing matched related donor allogeneic stem cell transplantation, he finally succumbed to his illness. As survival expectations for CLL have substantially improved (1), long-term complications of chemotherapy emerge, including secondary myeloid neoplasias (5). Recently, the largest series of AML/myelodysplastic syndrome after frontline FCR chemotherapy for CLL (5) reported an estimated incidence of 4.5% after follow-up of 44 months, a latency period of 35 months and median survival of 7 months. Abnormal cytogenetics were recorded in 96% of cases, most frequently unbalanced partial or complete loss of chromosomes 7 and/or 5. None had 11q23

Hodgkin lymphoma of the gastrointestinal tract in patients with inflammatory bowel disease: Portrait of a rare clinical entity

Patients with inflammatory bowel disease (IBD) on immunosuppression are at risk of developing lymphoma, particularly primary gastrointestinal (GI) tract non-Hodgkin lymphoma. Primary GI Hodgkin lymphoma (HL) in this setting, however, is rare and poorly defined. Here we review the available literature and also report a patient with Crohns disease (CD) who developed GI HL. Our search yielded 12 single case studies and 7 case series involving 22 patients published between 1978-2016. Twenty-one (91%) patients had CD, and 2 had ulcerative colitis. The median age at lymphoma diagnosis was 39 years, and 18 (78%) patients were males. HL was diagnosed at a median of 8 years after IBD detection and 2 years after commencing immunosuppression. HL had a predilection (80%) to involve the inflamed GI site and the histological subtype was mixed cellularity in 65% of cases. In-situ hybridization for Epstein-Barr virus (EBV)-encoded RNA was positive in all documented cases. HL was diagnosed in stages I, II, IV in 35%, 20% and 45% of the patients, respectively. Notably, 66% of patients with advanced disease had liver involvement. Immunosuppression was stopped in most (69%) patients at HL diagnosis. Treatment used was either chemotherapy only, surgery followed by chemotherapy, or surgery alone in 50%, 33% and 16% of cases, respectively. Four patients had an IBD flare during HL remission. Patients with IBD who develop GI HL have distinct characteristics; male sex, predominance of CD, preference to develop in inflamed sites, mixed cellularity histology, EBV positivity, and a unique spread to the liver pattern.

CT findings are highly predictive for perforation in patients with diffuse large B-cell lymphoma involving the intestines

Abstract Patients with diffuse large B-cell lymphoma (DLBCL) presenting with intestinal involvement are prone to develop perforation. Identification of those who are at high risk for this complication would enable a rational-based decision regarding preemptive surgery. Although computed tomography (CT) is widely used at diagnosis, data regarding its ability to predict intestinal perforation are scanty. We performed a retrospective single-center study, including all consecutive DLBCL patients presented with intestinal involvement, assessing predictors for perforation with an emphasis on CT-related parameters. Forty-nine patients were included, 43 (88%) underwent CT scan at diagnosis. Ten patients (20%) developed intestinal perforation. A univariate regression analysis found increased risk among patients with a concentric, transmural lesion, and a longer involved intestinal segment. In conclusion, CT scan results can define patients with DLBCL and intestinal involvement who are at risk for perforation, suggesting that a preemptive surgical resection should be considered in these cases.

Medical Cannabis Use by Hodgkin Lymphoma Patients: Experience of a Single Center

Hodgkin lymphoma (HL) is one of the most curable malignancies. Despite its effectiveness, chemotherapy is often associated with adverse events (AEs) such as nausea, anorexia, and impairment of general well-being. Our objective was to assess the extent of medical cannabis use among HL patients and evaluate its efficacy in controlling chemotherapy-related AEs. Patterns of medical cannabis use and efficacy were evaluated using physician-completed application forms, medical files, and patient-completed questionnaires, for all consecutive adult HL patients treated at the Tel-Aviv Medical Center between June 2010 and November 2016. One-hundred and thirty-three patients met the inclusion criteria. The median age of the cohort was 37 years, 53% were male, 46% were diagnosed at an early stage, and 88% achieved a complete response to treatment. Fifty-one patients (38%) used medical cannabis. There were no significant differences in baseline characteristics between cannabis users and nonusers. Cannabis users reported improvement in pain, general well-being, appetite, and nausea in 94, 87, 82, and 79% of cases, respectively. Importantly, 81.5% reported a high overall efficacy of cannabis in relieving symptoms. AEs related to cannabis use itself were mild. Thus, medical cannabis use is prevalent in this HL cohort, and appears to be effective in ameliorating chemotherapy-related AEs.