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Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p< 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Patients with Gaucher disease (GD), a rare autosomal recessive glycosphingolipid storage disease, commonly present to hematologists with unexplained splenomegaly, thrombocytopenia, anemia, and bone symptoms. Patients with GD may develop other manifestations, such as autoimmune thrombocytopenia, monoclonal gammopathy, multiple myeloma, or, even more rarely, other hematological malignancies; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with GD have significantly evolved over the last 30 years, some patients remain poor responders to GD-specific therapy, needing novel and investigational therapies. Ideally, patients with GD, like patients with other rare diseases, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The hematology community should be knowledgeable regarding the presentation and the variety of hematologic complications and comorbidities associated with Gaucher disease.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p< 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT.

Introduction:In previously untreated patients with chronic lymphocytic leukemia (CLL), treatment with ibrutinib plus rituximab improved progression-free survival (PFS) and overall survival (OS) compared to the standard fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapeutic regimen, based on the results of the phase III ECOG-E1912 trial. The improvement in PFS with ibrutinib plus rituximab was observed in patients with unmutated immunoglobulin heavy chain variable region gene (IGHV) but not in those with an IGHV mutated profile. However, the efficacy of ibrutinib compared to FCR has not yet been investigated in the real-world setting.

The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situhybridization; TP53gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53aberrations [del(17p) 27.6%, TP53mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL.

Background:The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL).

Herishanu: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.

Tadmor: PFIEZER: Consultancy; JNJ: Consultancy; ABBVIE: Consultancy; NOVARTIS: Consultancy; ROCHE: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Herishanu:ROCHE: Research Funding; JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding; JNJ: Consultancy. Rahimi-Levene:ABBVIE: Consultancy. Ruchlemer:ABBVIE: Consultancy; JNJ: Consultancy. Fogl:The Binding Site Group Ltd: Employment. Polliack:ROCHE: Research Funding; ABBVIE: Consultancy. Magal:The Binding Site: Employment. Townsend:The Binding Site Group Ltd: Employment.

Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; NOVARTIS: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy. Herishanu:JNJ: Consultancy; ABBVIE: Consultancy; ROCHE: Research Funding. Bairey:ROCHE: Research Funding; AbbVie: Consultancy; Jansen: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Rahimi-Levene:ABBVIE: Consultancy. Fineman:ABBVIE: Consultancy; JNJ: Consultancy. Ruchlemer:JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:JNJ: Consultancy; ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

Background: Invasive fungal infections (IFI) are life threatening infections reported mainly in acute leukemia patients with prolonged deep neutropenia and patients post bone marrow or organ transplants.

Bairey: Janssen: Consultancy.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Ruchlemer: Roche: Research Funding.

Richter's syndrome (RS) is the rare development of an aggressive lymphoid malignancy in a patient with pre-existing, or concomitant chronic lymphocytic leukemia (CLL). This complication occurs in about 5 % of patients with CLL, and the most frequent form is the development of diffuse large B-cell lymphoma (DLBCL) and less frequently Hodgkin lymphoma (HL) or prolymphocytic leukemia (PLL). Most of the available data on RS is derived from case reports or small series of patients, and only a few larger cohorts have been published.The purpose of this retrospective study was to summarize our experience with RS in CLL, examine possible risk factors and analyze relevant demographic, laboratory and clinical parameters, including outcome.We collected a total of 119 patients diagnosed with RS from 12 medical centers in Israel during the period 1971-2010.We then summarized clinical, demographic and some biological features related to CLL at diagnosis and examined possible risk factors for their transformation to RS.Of the 119 patients with RS, 61 % were males, 82% developed DLBCL, 14% HL and 4% PLL. In terms of ethnicity: 95% were Jews (64% Ashkenazi) and only 5 % were Arabs, which is similar to the reported data for CLL in Israel.The median time from CLL diagnosis to development of RS was 60 months (range, 0-182 months), and the median overall survival from diagnosis of RS was 9.5 months;34 % of the cases developed extranodal RS, and the most frequent sites of involvement were the gastro-intestinal tract and bone marrow. These results further confirm that there are no established “sanctuary sites” of extranodal RS, which can develop in all tissues and organs.None of the conventional clinical and laboratory parameters examined and evaluated as possible risk factors in CLL were able to predict transformation to RS, including: occurrence of autoimmune phenomenon during the course of CLL, spleen size, serum beta 2 microglobulin levels, degree of CD38 positivity, and the number of previous treatments given for CLL, or the prior use of rituximab in these regimens.The only parameters, present at the time of RS diagnosis which were found to correlate with adverse prognosis, included: performance status>2 (HR- 3.45), high IPI (HR- 3.28) and high Richter score (HR-7.45). In regard to therapy for RS, patients treated with chemotherapy followed by autologous stem cell transplantation (ASCT) had a better outcome with improved overall survival (p=0.034) (Figure).RS remains a heterogeneous entity. In this large series of patients none of the conventional clinical, epidemiological or laboratory parameters, often evaluated as possible prognostic factors in CLL, were associated with the risk of transformation to RS. In this retrospective study molecular genetic data were not available to examine their possible significance, as reported recently in other series.In terms of therapy, prior treatment of CLL with rituximab – containing regimens did not appear to impact the eventual outcome of patients who developed RS. On the other hand, ASCT did significantly improve overall survival in patients who had transformation to RS.On behalf the Israeli CLL study Group.No relevant conflicts of interest to declare.

Abstract 1340This icon denotes a clinically relevant abstract

Drug metabolism and disposition genes have a substantial impact on the pharmacology of many medications. For CML, the human organic cation transporter (hOCT1) actively transports imatinib mesylate (IM) into cells, thus is a crucial factor in the response to IM therapy, without a known effect on plasma levels. A number of single nucleotide polymorphisms (SNPs) are believed to affect the activity of hOCT1 and therefore may influence IM accumulation in cells. We therefore studied hOCT1 SNPs and correlated with IM plasma levels and clinical response to IM. We studied a SNP in exon 2 of hOCT1 (480C>G, Phe160Leu, rs683369), which, in the homozygous state (GG), has been associated with treatment failure on IM (DH Kim, Clin Cancer Res., 15:4750, 2009), and a SNP in exon 7 (1222A>G, Met408Val) which has been hypothesized as having increased activity (A Giannoudis, Haematologica 96(s2):87, 2011). Both of these are prevalent SNPs; the exon 2 SNP is found in 22% of Caucasians and the exon 7 SNP, in 60% of Caucasians (R Kerb, Cancer Letters 234:4, 2006).We studied 48 patients with CML in chronic phase (M:F 21:27 aged 17–89 years. Time since CML diagnosis was between 10 months and 18 years. IM therapy was between 10–128 months' duration. Most of the patients were on a dose of 400 mg/once daily, with the exception of 11 patients who were on doses >400 mg/once daily (mean 609.1 mg/day +/− 70.1 mg), and 9 patients, whose dose was <400 mg/once daily (mean 281 mg/day +/− 35.4 mg). Trough IM levels were performed by Novartis Pharmaceuticals on samples taken 24 hours after last dose, reported in ng/ml. Compliance was verified by a patient diary during the trough drug testing period, but not throughout the entire period of IM therapy. Genotyping for hOCT1 SNPs was performed on 36 patients. The exon 2 SNP was detected by PCR amplification and Dde I restriction enzyme analysis. The exon 7 was detected by PCR and restriction with BmgB1. Detailed molecular data was available on 36 patients, and partial molecular data on 8 others. Complete molecular remission (CMR) was defined as PCR negativity using RT-PCR until 2004, and thereafter, using a highly sensitive real time PCR assay.The mean IM trough level for all 48 patients was 1,153.0 (+/−493.1). There was much variation between IM levels in individual patients and levels also varied by dose. Patients who were on 400 mg/day had a mean IM level of 1064.1 (+/− 399.2). Patients on higher IM doses (>400 mg) had IM levels averaging 1397.2 (+/− 493.1). Patients on doses <400 mg/day had mean IM levels of 1057.3 (+/− 667.0), which was nearly identical to that of patients on 400 mg/day. Genotyping for the hOCT1 exon 2 SNP demonstrated that 66.7% of the 36 patients analyzed were homozygous for the wild type allele, 13.9% were heterozygous for the polymorphism and 19.4% were homozygous polymorphic. GG homozygotes had higher IM levels than CG/CC genotypes (1562.75 +/− 560 compared to 1310.6 +/− 470). This is because the patients were on doses greater than 400 mg/day (mean 483 mg/day compared to 405 mg/day). These patients took an average of 8.8 months to achieve a molecular CR and one transiently lost molecular CMR. Genotyping for the hOCT1 exon 7 SNP demonstrated that 47% of the 36 patients analyzed were heterozygous AG for the polymorphism and 53% of the patients were GG homozygotes. IM levels for the GG homozygotes were higher than for AG heterozygotes (1413 +/− 549.6 compared to 1254.0 +/− 393.9 ng/ml), despite the fact that they were on a slightly lower average dose (mean: 390.1 mg/day compared to 436.7 mg/day). For 13 of these GG homozygous patients, detailed molecular followup was available. Two of these patients never achieved CMR and 2 transiently lost CMR. The time to achieve complete molecular remission was generally long, 17.6 months (range 3–83 months). Importantly, 12 out of 13 of these patients with unsatisfactory clinical responses to IM were CC or CG at the exon 2 SNP, which are considered favorable genotypes for IM response (DH Kim, Clin Cancer Res., 15:4750, 2009).These data may suggest that the GG genotype for exon 7 in hOCT1 (rs628031), independent of the exon 2 (rs683369) genotype, is an adverse prognostic parameter despite adequate IM levels. These patients may be candidates for an alternate tyrosine kinase inhibitor. Further studies are necessary on larger groups of patients to confirm these results, which are important in view of the high frequency of the polymorphic rs628031 allele.Cohen: Novartis Pharmaceutical Company: Research Funding. Rund:Novartis Pharmaceutical Company: Honoraria, Research Funding.

Zimran: Actelion: Honoraria.

No relevant conflicts of interest to declare.

Israel has a variety of distinct ethnic groups and a high incidence of CLL, particularly in patients of European origin (Ashkenazi Jews). Recently we have examined 82 CLL patients who had FISH performed in 4 centers from different areas in Israel in an attempt to see if the results varied by ethnic origin. The patients were divided into 4 ethnic groups: - Asheknazi Jews -North African Jews (including Spanish origin, Bulgaria, Western Turkey and Greece), Eastern Jews (Iraq, Iran, Azberjian, India, Kurdistan, Eastern Turkey, Yemen and Egypt) and - Arab descent (this group was too small to further divide). Ashkenazi Jews comprised 65.8% of the patients, North Africans 15.8%, Eastern Jews 14.6%, Arabic patients 3.7%. Variations of clinical and biological parameters by ethnic groups are recorded in table 1, and the distribution of FISH aberrations by ethnic groups in table 2. Seventy four percent of patients had FISH abnormalities. Trends suggestive of ethnic variations of FISH abnormalities were observed, but none reached statistical significance due to the small number of patients. These initial results warrants continuation of this ongoing multicenter study. Variations of clinical and biological parameters of CLL patients by ethnic groups Ashkenazi N African Eastern Arabic Total No. patients 54 (65.8%) 13 (15.8%) 12(14.6%) 3(3.7%) 82 Median age (range) 67 67 60.5 57 65(35–82) Male:Female 1.7:1 1.6:1 3:1 2:1 1.86:1 Time from diagnosis 59.4(1–170)m 99.3m 80.5(9–202) 32(17–177)m 60.4 m Splenomegaly 55% 46% 40% 100% 39/75(52%) Lymphadenopathy 56% 31% 70% 100% 40/75(53%) Treated 73% 60% 60% 100% Zap70≥ 20% 11/25(44%) 1/7(14%) 33% 100% 17/42(40.5%) CD38>30 12/32(37.5%) 1/8(12.5%) (1/9)11% 100% 17/65(26%) FISH 13q del 21(38.9%) 4/12(33%) 42% 33 36% Trisomy 12 24% 2/12(16.7%) 16.7% 0 22% 11q23 del (ATM) 17% 0 16.7% 0 13% 17p13 del (p53) 13% 2/13(15%) 33% 33% 16% Normal 24% 38% 15% 33% 26% ≥ 2 abnormalities by FISH 9 (16.7%) 0 33% 0 12/81(15%) The distribution of FISH abnormalities in CLL patients by ethnic groups 13q− 12+ 11q− 17p− Normal No. patients 82 31 16 11 15 21 Ashkenazi 65.8% 21(68%) 11(69%) 9(82%) 6(40%) 13(62%) N Africans 15.8% 4(13%) 2(13%) 0 3(20%) 5(24%) Eastern Jews 14.6% 5(16%) 2(13%) 2(18%) 5(33%) 2(10%) Arabic 3.7% 1(3%) 0 0 1(7%) 1(5%) ≥ 2 abnormalities 12 (15%) 9 (29%) 3 (19%) 7(64%) 5(33%) 0

Monoclonal proteins(MPs) can frequently be detected in the serum/urine of chronic lymphocytic leukemia(CLL) patients. Serum free light chains(FLC) assays can detect MPs in the absence of M bands on immunofixation(IMF).An abnormal FLC ratio indicates excess of one light chain type suggesting clonality.We evaluated fresh serum/urine samples from 34 CLL patients at various stages of disease by quantitative nephelometric assay,IMF and FLC assay.Median age was 66 yrs(43–87),M:F 1.9:1 and median time from diagnosis 41.5 mos(5–288). 45% had advanced stage and 39% prior treatment with 1–7 therapies.Only 2 patients had mild renal failure.Serum immunoglobulins were normal/low in 94% of patients:IgG (171–1580 mg/l, median 803 mg/l), IgA(<25–310 mg/l, median 88 mg/l),IgM(<18–290 mg/l, median 38 mg/l), irrespective of the presence of a monoclonal protein. 71% of patients had evidence of abnormal immunoglobulin synthesis: by IMF alone (8),IMF and FLC(10) or FLC alone(8).Abnormal FLC ratios were more frequently associated with advanced stage disease and increased κ chains(see table 1). Abnormal FLC ratios(< 0.26 or >1.65) were measured in 18(53%) patients, 8 of whom did not have MPs by IMF. Two advanced stage patients had abnormal FLC ratios due to very low levels of a single light chain, most probably reflecting secondary hypogammaglobulinemia due to CLL and/or chemotherapy.Abnormal FLC ratios reverted to normal after 1 course of chemotherapy(FC+/−R) in 3 patients despite persistence of minimal residual disease(MRD).FLC were of the same type as expressed on the surface of CLL cells, with discrepancies observed in 5 patients.BM biopsy staining for light chains revealed IgAκ MGUS in addition to λ chain restricted CLL in one patient, but was noncontributory in the other 4. Conclusions: Neither IMF nor the FLC assay alone could detect all MPs. Normal FLC ratios do not exclude the presence of MPs. The FLC ratio should be interpreted with caution in CLL patients with advanced disease and hypogammaglobulinemia. Monoclonal bands and abnormal FLC ratios can be detected despite normal or low levels of serum immunoglobulins in CLL patients. The significance of these monoclonal gammopathies in CLL is not clear and warrants further study in a larger group of patients. Discrepancies between surface immunoglobulins and serum/urine MPs might suggest the presence of an additional condition:ex. MGUS. FLC may not be a sensitive measure of MRD. Normal FLC ratio Abnormal FLC ratio P value *median No. patients 16(47%) 18(53%) M:F 1.3:1 3.5:1 NS Age* 62.5 yrs(49–73) 68 yrs(43–87) NS Time from CLL diagnosis* 25.3 mos(0–282) 59 mos(0–210) NS Adv stage(Rai III/IV-Binet C) 25% 66.7% 0.018 Untreated 62% 50% NS CLL:κ:λ restriction 7:8(0.88:1) 11:6(1.8:1) NS Monoclonal protein 8(50%) 10(56%) NS Increased freeκ no. 8 15 0.043 Freeκ level* 19.6(4.5–200) 39.2(2.9–386) 0.0064 Increased freeλ no 4 3 NS Free λ level* 19.3(12.4–146) 15.4(0.1–517) NS Serum β 2m* 3.1(1.8–6.7) 4.3(2.2–10.2) NS Zap70≥20 86% 36% 0.002 CD38≥30 44% 44% NS 17pdel/11qdel 40% 44% NS

Biphosphonates (zoledronate, pamidronate and clodronate) are frequently used for bone disease prevention and treatment in patients with multiple myeloma. Monthly biphosphonate therapy improves quality of life and in some reports survival. However, biphosponates are associated with adverse effects such as renal impairment and osteonecrosis of the jaws. We have recently described 3 myeloma patients who developed oseomyelitis of the jaw during chronic biphosphonate therapy. In a national survey we found 11 patients from 6 centers in Israel with osteomyelitis of the jaws probably due to prolonged therapy with intravenous biphosphonates. Nine were female. Median age at the time of diagnosis of myeloma was 67 years (range 59–86). nine patients suffered from IgG myeloma, and 2 had light chain disease. In five patients MGUS was known during 4 to 9 years before development of overt myeloma. All patients had received chemotherapy, and 2 underwent ABMT. Median time from diagnosis of myeloma to diagnosis of osteomyelitis of the jaw was 30 months (range 15–48). In six cases osteomyelitis was provoked by dental procedure. In all cases the diagnosis of osteomyelitis was confirmed by bone biopsy and in 7 colonies of Actinomyces Israeli were demonstrated. In one patient Pseudomonas Aeruginosa was also found. All patients had been treated with biphosphonates before diagnosis of osteomyelitis (13 to 48 months): eight with pamidronate, and 3 with zoledronate. The mean total dose of pamidronate was 3190 mg (range 1690–4680), and zoledronate- 72mg (range 16–96). Therapy for osteomyelitis included prolonged antibacterial treatment, surgical debridment, and hyperbaric oxygenation. Acute, and chronic, osteomyelitis of the jaws secondary to biphosphonate therapy, is frequently encountered among myeloma patients and should be reported separately from another complication of biphosphonates, osteonecrosis of the jaws.

Rituximab has revolutionized the treatment outcome of non-Hodgkins lymphoma (NHL) patients but its role in retreatment in all NHL patients is not yet established. Therefore, the Israel Rituximab Retreatment Study Group was organized in order to summarize retrospectively the treatment results of B-cell NHL patients who received ≥ 2 rituximab treatments. Eighty-eight NHL patients from 13 medical centers were enrolled, 39 males, 49 females with a mean age of 57.3 years (range 26–88). Sixty-four patients (73%) had indolent lymphoma (21- follicular grade I, 17 follicular grade II, 10-follicular grade III, 9-small lymphocytic, 6- MALT, 2- marginal zone, 1-lymphoplasmacytic). Eighteen patients (20%) had aggressive lymphoma [diffuse large B-cell lymphoma (DLBCL)] and 6 patients had mantle cell lymphoma. Fifty-nine patients received one regimen of chemotherapy and 23 patients received 2 chemotherapy regimens before the first treatment with rituximab. There was no significant difference in the median time to progression (TTP) after the first rituximab treatment whether the patient received no previous chemotherapy or 1 or 2 previous chemotherapy regimens (12 vs 12 vs 14 months, respectively). All patients received 2 courses of rituximab, 33 patients-3 courses, 6 patients -4 courses and 2 patients-5 courses, with a mean of 4.4 doses in each course (range 1–8). Only 45 patients received any treatment after the second course of rituximab. The first course of rituximab was administered alone in 46 patients and with chemotherapy in 42 (24 CHOP, 6 COP, 6 FC, 2 chlorambucil, 1 LMP, 1 DVIP, 1 ESHAP, 1 MACOP-B). There was no difference in the median time to next treatment (TTNT) whether the rituximab was given alone or with chemotherapy (16 and 14 months, respectively). The second course of rituximab was administered alone in 46 patients and with chemotherapy in 42 patients (13 CHOP, 11 FC, 6 COP, 5 ICE, 3 ESHAP, 2 HyperCVAD, 1 CNOP 1 VEEP). The addition of chemotherapy did not change the overall response (CR and PR) to the second rituximab treatment (72% in rituximab alone vs. 69% in rituximab with chemotherapy, in indolent lymphoma patients 76% vs. 72%, in aggressive lymphoma patients 70% vs. 62.5%, respectively). TTP after the second rituximab treatment was similar or possibly longer than after the first treatment (median 14 and 12 months, mean 23.4 and 16.2 months respectively).

Complete responses (CR) of up to 95% have been reported with both pentostatin and cladribine in patients with hairy cell leukemia (HCL). Although responses are durable, relapses occur even 10 years after treatment. No trial has compared pentostatin to cladribine for HCL. Furthermore, few series achieve sufficient maturity to answer the question: can these agents induce a cure in HCL? We reviewed retrospectively 219 patients with HCL (median follow up (FU) from diagnosis: 12.6 years) to compare pentostatin with cladribine in the treatment of HCL, and to assess the potential for cure in this disease. Diagnosis of HCL and exclusion of HCL-variant were confirmed by central review. Overall response to 1stline pentostatin (n=185) was 96% with CR of 81% and median FU of 10.8 (range 0.3–17.9) years. Response to cladribine was 100% with CR of 82%. No significant difference in response was seen with cladribine (n=34) at median FU of 7.2 (range 0.5–11.5) years. Median disease free survival (DFS) for both agents was 10 years. 38% of patients relapsed 4.9 (range 1–16) years and 4.4 (range 1–10) years after treatment with pentostatin and cladribine, respectively. Although responses were maintained for pentostatin and cladribine when used at 2nd(94% and 100% respectively) and 3rdline (100% and 100% respectively) treatment, CR decreased significantly with each sequential relapse through 70% to 45% (p≤0.01). Attainment of CR at 1st line treatment was significantly associated with increased DFS (p=0.000) as compared to those achieving only partial response (PR).