Risk factors and outcomes of COVID-19 in adult patients with hematological malignancies: A single-center study showing lower than expected rates of hospitalization and mortality.

BACKGROUND: Studies addressing coronavirus disease 2019 (COVID-19) in patients with hematological malignancies have reported mortality rates of up to 40%; however, included predominantly hospitalized patients. METHODS: During the first year of the pandemic, we followed adult patients with hematological malignancies treated at a tertiary center in Jerusalem, Israel, who contracted COVID-19, with the aim of studying risk factors for adverse COVID-19-related outcomes. We used remote communication to track patients managed at home-isolation, and patient questioning to assess the source of COVID-19 infection, community versus nosocomial. RESULTS: Our series included 183 patients, median age was 62.5 years, 72% had at least one comorbidity and 39% were receiving active antineoplastic treatment. Hospitalization, critical COVID-19, and mortality rates were 32%, 12.6%, and 9.8%, respectively, remarkably lower than previously reported. Age, multiple comorbidities, and active antineoplastic treatment were significantly associated with hospitalization due to COVID-19. Treatment with monoclonal antibodies was strongly associated with both hospitalization and critical COVID-19. In older (≥60) patients not receiving active antineoplastic treatment, mortality, and severe COVID-19 rates were comparable to those of the general Israeli population. We did not detect patients that contracted COVID-19 within the Hematology Division. CONCLUSION: These findings are relevant for the future management of patients with hematological malignancies in COVID-19-affected regions.

Response rates of extra-nodal diffuse large B cell lymphoma to anti-CD19-CAR T cells: A real word retrospective multicenter study.

Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)-only and 12 of 126 (10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8-13.6] vs. 14.1 [95% CI: 10-18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5-18.2] vs. 18.4 [95% CI 14.8-22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9-15.5] vs. 4.28 months [95% CI 0.6-7.9], p = .010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4-19.6] vs. 8.7 months [95% CI 4.6-12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.

Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis.

OBJECTIVE: Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. METHODS: Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. RESULTS: Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. CONCLUSIONS: Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.

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

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.

Favorable outcome of primary mediastinal large B-cell lymphoma patients treated with sequential RCHOP-RICE regimen without radiotherapy.

PURPOSE: Outcomes in primary mediastinal B cell lymphoma (PMBL) improved with the introduction of dose intense treatments, consolidation radiotherapy and rituximab. DA-EPOCH-R, which omits radiotherapy has been adopted with worldwide enthusiasm, despite lack of proven superiority in randomized trials. We aimed to evaluate the course and outcome of PMBL using an alternative intensive rituximab-containing regimen, RCHOP-RICE. We also evaluated the prognostic value of (18)FDG-PET-CT (PET-CT). METHODS: We reviewed the clinical, laboratory and imaging data of PMBL patients receiving 1st-line treatment in Hadassah Medical Center between 8/2002 and 10/2014. RESULTS: Of 47 PMBL patients, 24 (51 %) were treated with RCHOP-RICE and 23 (49 %) with other protocols. Overall, the 5-year progression-free survival was 93 % and the overall survival was 98 % (87 and 100 %, respectively, for the RCHOP-RICE regimen). Patient characteristics and treatment toxicities were balanced among protocols. A mean of 11.1 ± 1.3 hospitalization days/patient were needed to administer RCHOP-RICE regimen compared to 37 ± 2 days/patient for DA-EPOCH-R (n = 2). Radiotherapy was given to 3 patients (12 %) treated with RCHOP-RICE compared to 18 patients (78 %) treated with other protocols (p < 0.01). For patients followed with interim and end of treatment (EOT) PET-CT, we observed a significant reduction in the uptake between the two (p < 0.0001). Using a Deauville score cutoff of 3, the negative and positive predictive values (NPV and PPV) of EOT PET-CT were 94 and 33 %, respectively. CONCLUSIONS: The RCHOP-RICE protocol results in excellent survival outcomes, generally permits omission of RT and is simpler to administer than DA-EPOCH-R. Interim PET-CT in PMBL may be unjustified; however, EOT Deauville scores ≤3 predicts a favorable outcome.

Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia.

The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.

A 10-year experience with treatment of high and standard risk Hodgkin disease: six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved.

Therapy of Hodgkin lymphoma (HL) is designed to prolong survival and minimize toxicity. A total of 124 patients with newly diagnosed HL and adverse prognostic factors were prospectively studied between July, 1999 and August, 2005. Patients with early unfavorable and advanced disease were eligible for the study. Patients were assigned to therapy based on international prognostic score (IPS). Those with IPS ≥ 3 received three cycles of escalated BEACOPP (EB). All others received two cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned according to early interim GA(67) or positron emission tomography (PET)/computerized tomography (CT). Four cycles of EB or SB were administered following a positive or negative scan, respectively. Complete remission rate, 10-year progression free (PFS), and overall survival (OS) were 97, 87, and 88%, respectively, at a median follow-up of 89 months (5-144). PFS and OS were similar in both groups. Fertility status was assessed in 38 females aged <40 years; 94% of females younger than 40 years preserved their cyclic ovarian function. Nineteen conceived during follow-up for 30 pregnancies, delivering 24 babies. Deliveries were reported up to 7 years from diagnosis. Predictive value of negative interim Ga(67) or PET/CT was 87 and 93%, respectively. Six cycles of tailored BEACOPP, for patients with adverse prognostic factors, provide encouraging long-term PFS and OS, and fertility is preserved in most females.

Evidence for clinical and genetic heterogeneity in hereditary benign telangiectasia.

BACKGROUND: Telangiectases are abnormal dilatations of end vessels in the subpapillary plexus of the papillary dermis. Hereditary benign telangiectasia (HBT) (OMIM 187260) is a genetic skin disorder, characterized by multiple cutaneous telangiectases appearing in the first years of life in various locations. Several familial cases of HBT have been described displaying autosomal dominant inheritance. In some of the described pedigrees, telangiectases are limited to sun-exposed areas, whereas in others lesions are randomly distributed over the body. The disorder has been previously mapped to a 7Mb interval on chromosome 5q14 (CMC1 locus) in an Italian pedigree with randomly distributed telangiectases. OBJECTIVES: A large pedigree of HBT with photodistributed lesions is described. We sought to determine whether photodistributed HBT is linked to the CMC1 locus. METHODS: In all, 35 family members were examined. DNA was extracted from blood and saliva samples. Linkage analysis to CMC1 locus on chromosome 5q14 was screened by using 3 polymorphic markers. RESULTS: In all, 23 family members were found to have variable numbers of cutaneous radiating macular telangiectases, measuring 1 to 3 cm and distributed over the face, back of the hands, and forearms. HBT in this family is inherited in an autosomal dominant pattern with incomplete penetrance. Linkage to the CMC1 locus was excluded. LIMITATION: Only one family, although very large, was studied in this project. CONCLUSIONS: Clinical and genetic heterogeneity is evident in HBT. Photodistributed HBT is not related pathogenically to capillary malformations or to randomly distributed hereditary telangiectases and should be recognized as a separate entity.

Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome.

Therapy of Hodgkin disease (HD) is designed to prolong progression-free survival and minimize toxicity. The best regimen to achieve this has not yet been defined. A total of 108 patients with newly diagnosed HD and adverse prognostic factors were prospectively studied between 1999 and 2004. They were assigned to therapy according to defined risk stratification. Patients were defined depending on the International Prognostic Score (IPS). Those with IPS of 3 or higher received 2 cycles of escalated therapy, including bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [EB]). All others received 2 cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned following 2 cycles according to results of early interim 67Ga or positron emission tomography/computed tomography (PET/CT). Following a positive interim scan, 4 cycles of EB were administered, whereas 4 cycles of SB were given to patients with a negative scan. The complete remission rate, the 5-year event-free survival (EFS), and overall survival (OS) rates were 97%, 85% and 90%, respectively. Relapse or progression occurred in 27% of patients with interim positive PET/CT versus 2.3% of negative scans (P<.02). Early interim fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT is a useful tool for adjustment of chemotherapy on an individual basis. Similar EFS and OS rates were observed for patients in both risk groups.

Bleeding, obstruction, and perforation in a series of patients with aggressive gastric lymphoma treated with primary chemotherapy.

BACKGROUND: The management of patients with gastric lymphoma has evolved, with a shift toward nonsurgical treatment. The rates of surgical complications in patients receiving chemotherapy have been insufficiently studied. The objective of this study was to assess the frequency of bleeding, perforation, and gastric outlet obstruction in patients who received chemotherapy as primary treatment for gastric diffuse large B cell lymphoma (DLBCL). METHODS: We reviewed files of all patients with gastric DLBCL who were diagnosed and treated primarily with chemotherapy in our hospital between 1990 and 2005. RESULTS: Eighteen (25%) of 73 patients experienced surgical complications, of whom 6 (8%) underwent surgery. Eight patients (11%), six with active lymphoma, experienced gastric bleeding; one required gastrectomy. Eight patients (11%) developed gastric outlet obstruction, of whom three were treated conservatively, three required surgery, one stopped treatment, and one received further chemotherapy. Six of the eight patients had no evidence of active lymphoma at the time of obstruction. Two additional patients underwent gastrectomy due to resistant or relapsed disease. Gastric perforation was not observed. Median survival was 90 months for the entire series, 94 months for patients with gastric outlet obstruction, and 11.5 months for patients with gastric bleeding. CONCLUSIONS: Given the rate of surgical complications, especially gastric bleeding and gastric outlet obstruction, there is still an important role for the surgical consultant in the treatment of patients with gastric DLBCL receiving chemotherapy. Gastric perforation, although frequently cited as a complication, is in fact rarely observed.

Allergic reaction to chlorambucil in chronic lymphocytic leukemia presenting with fever and lymphadenopathy.

Chronic lymphocytic leukemia (CLL) is commonly treated with the alkylating agent chlorambucil. Allergic reactions to this chemotherapy are rare. Previous reports include urticaria, angioedema, rashes, toxic epidermal necrolysis, drug fever and one case of immune hemolytic anemia. We report 2 cases that had the identical symptoms of acute onset of high fever and progressive lymphadenopathy. These symptoms disappeared with conservative management. Neither of the patients were treated for infection or disease progression. When the patients were rechallenged with chlorambucil, identical reactions recurred. There was no cross-reactivity with the alkylating agent cyclophosphamide or other types of chemotherapy. This type of reaction to chlorambucil has not been described previously. It is important to recognize this as an allergic reaction. These reactions could be confused with the onset of infection, progression of disease or even a Richter's transformation.

Primary ALK positive anaplastic large cell lymphoma of the pancreas.

Here we present an unusual case of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALCL), appearing as a primary tumor of the pancreas which invaded into the adjacent duodenal wall, causing upper gastrointestinal bleeding. After complete resection of the tumor (Whipple's operation), the patient received 4 cycles of CHOP chemotherapy. Currently, 2 years after diagnosis the patient still remains lymphoma free. Primary ALCL of the pancreas is very rare and has only been reported on one previous occasion. Nevertheless, lymphoma should be considered in the differential diagnosis of pancreatic tumors and an attempt to obtain tissue diagnosis is always necessary before continuing with radical surgery, especially in young patients.

Large B-cell lymphoma manifesting as an invasive cardiac mass: sustained local remission after combination of methotrexate and rituximab.

Cardiac tumor is an infrequent but serious manifestation of lymphoma and optimal management has not been well defined in these rare cases. Here we describe a patient who after autologous transplant for large B-cell lymphoma, relapsed with an invasive cardiac tumor, infiltrating the full thickness of the right myocardial wall. During therapy, she developed hemodynamic collapse due to complex atrial arrhythmias and had to be treated and stabilized in the intensive cardiac care unit. Despite initial significant regression of the cardiac tumor, new extranodal sites of lymphoma soon appeared in the skin, stomach and nervous system. Because of poor compliance, she was given salvage therapy with weekly four i.v. infusions of methotrexate and rituximab followed by monthly four maintenance cycles of rituximab alone. This produced an unexpected prolonged complete remission lasting 12 months, but she then developed a fatal leukemic phase. The relapse spared the heart and no cardiac abnormality was evident clinically or by any imaging technique. To the best of our knowledge this case, unique in terms of tumor size and extent of invasion, represents the first report of the treatment of invasive cardiac lymphoma using a combination of modest chemotherapy and rituximab.

Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine-rituximab-containing regimens: natural history- or therapy-related complication?

Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occurring as a result of the above drug-induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large-cell transformation occurred during or shortly after the initiation of regimens containing these agents before transformation occurred. One patient had received rituximab alone, three fludarabine-containing regimens and five received sequential regimens containing both agents. This