Telemedicine During COVID-19 Pandemic: Lesson Learned from the Lazio Region Infectious Diseases and Emergency Department Network.

Telemedicine and teleconsultation can be powerful and useful tools for patients to hamper the physical barriers to access to health care services during COVID-19 pandemic. We describe the teleconsultation (TC) model in the Lazio Region. It uses a hub-and-spoke network system on geographic regional basis using a web based digital platform, termed ADVICE with the aim to connect regional Emergency Departments (EDs) and Infectious Diseases (ID) acute and critical care settings for patients with acute ID syndrome. Between January 2020 and June 2021, the ADVICE platform received 18.686 TCs: of them, 10838 requests (58%) were for ID TCs in 7996 patients, followed by 2555(13%) requests for trauma, 2286(12%) for acute complex syndrome and 1681 (8%) for Stroke TCs. Three quarter of ID TCs were requested for SARS-COV-2 infection, followed by sepsis management in 7% and tuberculosis in 6%. In 5416 TCs, 68%, diagnostic investigations and therapeutic prescriptions were recommended before admission, in 1941 TCs, 24%, the recommendation was patient admission and in 608 TCs, 7%, was to discharge patient at home. Telemedicine have ensured high-profile consultations for ID patients and during COVID-19 the use of this resource optimized clinical patient management.

Multi-omics approach to COVID-19: a domain-based literature review.

BACKGROUND: Omics data, driven by rapid advances in laboratory techniques, have been generated very quickly during the COVID-19 pandemic. Our aim is to use omics data to highlight the involvement of specific pathways, as well as that of cell types and organs, in the pathophysiology of COVID-19, and to highlight their links with clinical phenotypes of SARS-CoV-2 infection. METHODS: The analysis was based on the domain model, where for domain it is intended a conceptual repository, useful to summarize multiple biological pathways involved at different levels. The relevant domains considered in the analysis were: virus, pathways and phenotypes. An interdisciplinary expert working group was defined for each domain, to carry out an independent literature scoping review. RESULTS: The analysis revealed that dysregulated pathways of innate immune responses, (i.e., complement activation, inflammatory responses, neutrophil activation and degranulation, platelet degranulation) can affect COVID-19 progression and outcomes. These results are consistent with several clinical studies. CONCLUSIONS: Multi-omics approach may help to further investigate unknown aspects of the disease. However, the disease mechanisms are too complex to be explained by a single molecular signature and it is necessary to consider an integrated approach to identify hallmarks of severity.

COVID-19: viral-host interactome analyzed by network based-approach model to study pathogenesis of SARS-CoV-2 infection.

BACKGROUND: Epidemiological, virological and pathogenetic characteristics of SARS-CoV-2 infection are under evaluation. A better understanding of the pathophysiology associated with COVID-19 is crucial to improve treatment modalities and to develop effective prevention strategies. Transcriptomic and proteomic data on the host response against SARS-CoV-2 still have anecdotic character; currently available data from other coronavirus infections are therefore a key source of information. METHODS: We investigated selected molecular aspects of three human coronavirus (HCoV) infections, namely SARS-CoV, MERS-CoV and HCoV-229E, through a network based-approach. A functional analysis of HCoV-host interactome was carried out in order to provide a theoretic host-pathogen interaction model for HCoV infections and in order to translate the results in prediction for SARS-CoV-2 pathogenesis. The 3D model of S-glycoprotein of SARS-CoV-2 was compared to the structure of the corresponding SARS-CoV, HCoV-229E and MERS-CoV S-glycoprotein. SARS-CoV, MERS-CoV, HCoV-229E and the host interactome were inferred through published protein-protein interactions (PPI) as well as gene co-expression, triggered by HCoV S-glycoprotein in host cells. RESULTS: Although the amino acid sequences of the S-glycoprotein were found to be different between the various HCoV, the structures showed high similarity, but the best 3D structural overlap shared by SARS-CoV and SARS-CoV-2, consistent with the shared ACE2 predicted receptor. The host interactome, linked to the S-glycoprotein of SARS-CoV and MERS-CoV, mainly highlighted innate immunity pathway components, such as Toll Like receptors, cytokines and chemokines. CONCLUSIONS: In this paper, we developed a network-based model with the aim to define molecular aspects of pathogenic phenotypes in HCoV infections. The resulting pattern may facilitate the process of structure-guided pharmaceutical and diagnostic research with the prospect to identify potential new biological targets.

Detection of Viral RNA in Tissues following Plasma Clearance from an Ebola Virus Infected Patient.

An unprecedented Ebola virus (EBOV) epidemic occurred in 2013-2016 in West Africa. Over this time the epidemic exponentially grew and moved to Europe and North America, with several imported cases and many Health Care Workers (HCW) infected. Better understanding of EBOV infection patterns in different body compartments is mandatory to develop new countermeasures, as well as to fully comprehend the pathways of human-to-human transmission. We have longitudinally explored the persistence of EBOV-specific negative sense genomic RNA (neg-RNA) and the presence of positive sense RNA (pos-RNA), including both replication intermediate (antigenomic-RNA) and messenger RNA (mRNA) molecules, in the upper and lower respiratory tract, as compared to plasma, in a HCW infected with EBOV in Sierra Leone, who was hospitalized in the high isolation facility of the National Institute for Infectious Diseases "Lazzaro Spallanzani" (INMI), Rome, Italy. We observed persistence of pos-RNA and neg-RNAs in longitudinally collected specimens of the lower respiratory tract, even after viral clearance from plasma, suggesting possible local replication. The purpose of the present study is to enhance the knowledge on the biological features of EBOV that can contribute to the human-to-human transmissibility and to develop effective intervention strategies. However, further investigation is needed in order to better understand the clinical meaning of viral replication and shedding in the respiratory tract.

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Long-term efficacy and toxicity of rituximab plus fludarabine and mitoxantrone (R-FM) for gastric marginal zone lymphoma: a single-center experience and literature review.

There is no consensus about the best treatment option for patients with HP-negative gastric MALT lymphomas or persistent disease after HP eradication.We have investigated fludarabine and mitoxantrone with rituximab (R-FM) as first-line treatment. A cohort of 13 patients was analyzed. Induction treatment consisted of fludarabine (25 mg/m2 i.v. on days 2 to 4), mitoxantrone (10 mg/m2 i.v. on day 2), and rituximab (375 mg/m2 i.v. on day 1), for up to six cycles every 28 days. All patients achieved a complete remission, a median of four cycles was given. Treatment-related toxicities were mainly hematologic, with grade 3-4 neutropenia observed in 11/13 patients (84.6%). One patient had grade 3 febrile neutropenia, two patients developed prolonged pancytopenia (15%), and one patient experienced CMV reactivation at 2 months. After a median follow-up of 84 months, 1/13 had disease relapse and received total gastrectomy; estimated 10-year progression-free survival and overall survival were 92.4 and 100%, respectively. Our study suggests R-FM regimen has a high long-term efficacy for untreated HP-negative gastric MALT lymphoma patients and HP-positive patients who failed HP eradication. The elevated incidence of grade 3-4 hematological toxicity, yet manageable, makes this treatment less safe compared to rituximab in combination with chlorambucil or bendamustine.

Enabling Rapid Response to the 2014-2016 Ebola Epidemic: The Experience and the Results of the National Institute for Infectious Diseases Lazzaro Spallanzani.

The unprecedented epidemic of Ebola virus disease (EVD) in West Africa highlighted the need for stronger systems for disease surveillance, response, and prevention worldwide. Tackling an epidemic event today requires a broader view, not only limited to medical management of the patients, but which also includes heroic efforts by clinicians and public health personnel.Since its foundation in 1936, INMI has been devoted to the prevention, diagnosis and care for infectious diseases. In 2009, INMI became a WHO collaborative center for clinical care, diagnosis, response and training on Highly Infectious Diseases. This paper is aimed to present the activities and the challenging issues encountered by INMI during the 2014-2015 EVD outbreak in terms of preparedness and response to the epidemiological, clinical, diagnostic and research controversial aspects of EVD, both in Italy and in the field.

Short-term economic impact of the Zika virus outbreak.

Zika virus (ZIKV) is mainly transmitted by mosquitoes bites. However, transmission by sexual contacts has been reported in 11 non endemic countries. The rapid spread of ZIKV in Latin American and Caribbean Countries (LCR), person-to-person transmission and perceived risk on people's well being can affect the emerging economies of LCR which historically dependent on truism. Here we present an analysis on economic outputs for assessing the current impact of ZIKV on markets. Our analysis show an unexpected resilience of LCR markets to international alerts. This positive response represents an opportunity to scale-up interventions for preventing the further spreading of the ZIKV epidemic.

Ebola virus disease complicated with viral interstitial pneumonia: a case report.

BACKGROUND: In the current Ebola epidemic in Western Africa, many healthcare workers have become infected. Some of these have been medically evacuated to hospitals in Europe and the USA. These clinical experiences provide unique insights into the course of Ebola virus disease under optimized condition within high level isolation units. CASE PRESENTATION: A 50-year-old Caucasian male physician contracted Ebola virus diseases in Sierra Leone and was medically evacuated to Italy. Few days after the admission the course of the illness was characterized by severe gastro-intestinal symptoms followed by respiratory failure, accompanied by pulmonary infiltration and high Ebola viral load in the bronchial aspirate and Plasmodium vivax co-infection. The patient received experimental antiviral therapy with favipiravir, convalescent plasma and ZMAb. Ebola viral load started to steadily decrease in the blood after ZMAb administration and became undetectable by day 19 after admission, while it persisted longer in urine samples. No temporal association was observed between viral load decay in plasma and administration of favipiravir. The patient completely recovered and was discharged 39 days after admission. CONCLUSIONS: This is the first case of Ebola-related interstitial pneumonia documented by molecular testing of lung fluid specimens. This reports underlines the pivotal role of fluid replacement and advanced life support with mechanical ventilation in the management of patients with Ebola virus diseases respiratory failure. Beside our finding indicates a close temporal association between administration of cZMAb and Ebola virus clearance from blood.

Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.

In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

Mucocele of the appendix: case report of a rare disease with changing diagnostic-therapeutic behavior.

Mucinous appendicular neoplasms are a rare and heterogeneous group of tumors, whose treatment may vary based on histologic features and extent. We present a case of low-grade appendiceal mucinous neoplasm mimicking an acute appendicitis scenario. The patient underwent appendectomy along with resection of the caecal fundus. Choosing the correct treatment according to the case by following current guidelines is crucial to avoid under- or overtreatment.

The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma.

Several drugs used for diffuse large B-cell lymphoma (DLBCL) treatment rely on DNA damage for tumor cell killing. We verified the prognostic impact of the host DNA repair genotype in 2 independent cohorts of DLBCL treated with R-CHOP21 (training cohort, 163 cases; validation cohort, 145 cases). Among 35 single nucleotide polymorphisms analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival. DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (hazard ratio [HR] = 3.23; P < .001; q =0 .009) compared with patients carrying the AA genotype. Multivariate analysis adjusted for International Prognostic Index identified MLH1 AG/GG as an independent OS predictor (P < .001). The poor prognosis of MLH1 AG/GG was the result of an increased risk of failing both R-CHOP21 (HR = 2.02; P = .007) and platinum-based second-line (HR = 2.26; P = .044) treatment. Survival analysis in the validation series confirmed all outcomes predicted by MLH1 rs1799977. The effect on OS of MLH1, a component of the DNA mismatch repair system, is consistent with its role in regulating the genotoxic effects of doxorubicin and platinum compounds, which are a mainstay of DLBCL first- and second-line treatment.

Tuberculosis case finding based on symptom screening among immigrants, refugees and asylum seekers in Rome.

BACKGROUND: In Italy the proportion of cases of tuberculosis in persons originating from high-prevalence countries has been increasing in the last decade. We designed a study to assess adherence to and yield of a tuberculosis screening programme based on symptom screening conducted at primary care centres for regular and irregular immigrants and refugees/asylum seekers. METHODS: Presence of symptoms suggestive of active tuberculosis was investigated by verbal screening in migrants presenting for any medical condition to 3 free primary care centres in the province of Rome. Individuals reporting at least one symptom were referred to a tuberculosis clinic for diagnostic workup. RESULTS: Among 2142 migrants enrolled, 254 (11.9%) reported at least one symptom suggestive of active tuberculosis and 176 were referred to the tuberculosis clinic. Of them, 80 (45.4%) did not present for diagnostic evaluation. Tuberculosis was diagnosed in 7 individuals representing 0.33% of those screened and 7.3% of those evaluated for tuberculosis. CONCLUSION: The overall yield of this intervention was in the range reported for other tuberculosis screening programmes for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population. Further evaluation of this approach appears to be warranted.

Evaluation of residual CD34(+) Ph(+) progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy.

BACKGROUND: Compared with imatinib, nilotinib is a potent breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (bcr-abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34-positive, Philadelphia chromosome-positive (CD34(+) Ph(+) ) cells are detectable in about 45% of patients with CML, despite being on long-term imatinib therapy and having achieved sustained CCyR. METHODS: CD34(+) cells from bone marrow of de novo CML patients in the chronic phase (n = 24) treated with nilotinib (median duration of therapy, 22 months) were isolated and scored for BCR-ABL by fluorescent in situ hybridization (FISH) analysis. Similar analysis was also performed in 5 de novo CML chronic phase patients who achieved CCyR within 3 months of nilotinib therapy. RESULTS: FISH evaluation of a median of 100 CD34(+) nuclei per patient revealed that only 1 of 20 (5%) evaluable patients showed residual Ph(+) progenitor cells. In this patient, just 1 of 140 (0.7%) CD34(+) interphase nuclei was found to be positive for BCR-ABL. Surprisingly, no CD34(+) Ph(+) cells were found even in those 5 patients evaluated after 3 months of nilotinib treatment. CONCLUSIONS: This study assessed for the first time the persistence of CD34(+) Ph(+) cells during nilotinib first-line treatment. Preliminary results showed that in patients in CCyR, even after short-term nilotinib therapy, residual leukemic progenitors are very rarely detected compared with imatinib-treated CCyR patients. It is yet to be determined if these findings will have an impact in the path to a cure of CML with tyrosine kinase inhibitors.

Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients.

BACKGROUND: Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported. METHODS: We collected clinical and biological data of patients presenting with an osteo-dural or primary dural multiple myeloma (OD-DMM) or a central nervous system myelomatosis (CNS-MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). RESULTS: A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty-five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS-MM was 6 months, for OD-DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression-free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. ß2-Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with ß2-microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR. CONCLUSIONS: The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials.

IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia.

BACKGROUND: Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed. METHODS: Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, ß2-microglobulin levels, absolute lymphocyte count and number of lymph node regions. RESULTS: IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, ß2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high ß2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed. CONCLUSIONS: Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.

Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia.

Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.

Tuberculosis in sheltered homeless population of Rome: an integrated model of recruitment for risk management.

The authors show the results of an integrated model for risk management of tuberculosis in a sample of sheltered homeless in Rome. Tuberculin skin test (TST) was used for evaluating the prevalence of latent infection (LTBI). In TST positives, expectorate was collected and chest X-ray was achieved. Multiple logistic regression analysis was performed to investigate determinants of infection. Out of 288 recruited subjects, 259 returned for the TST reading; 45.56% were positive and referred to a specialized center; 70 accessed the health facility and completed the clinical pathway. The risk factors associated to LTBI were male gender (OR = 3.72), age over 60 years (OR = 3.59), immigrant status (OR = 3.73), and obesity (OR = 2.19). This approach, based on an integrated social network, guarantees high adherence to screening (89.93%), allowing patients testing positive for latent tuberculosis infection to be diagnosed and rapidly referred to a specialized center.

Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia.

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior.

Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.