A Case of Hemophagocytic Lymphohistiocytosis Triggered by Disseminated Tuberculosis and Hairy Cell Leukaemia after SARS-CoV2 Infection

Hemophagocytic Lymphohistiocytosis (HLH) is a rare but life-threatening disease that can occur either as a primary condition or as a consequence of a variety of triggers, including infectious diseases. Here we present a case of secondary HLH triggered by systemic Mycobacterium tuberculosis infection in a 59-year-old immunocompromised Hairy Cell Leukemia and previous SARS-CoV2 infected patient. This case report underlines the role of Etoposide-based chemotherapy in treating the severe inflammation that is the defining factor of HLH, suggesting how, even when such therapy is not effective, it may still give the clinicians time to identify the underlying condition and start the appropriate targeted therapy. Moreover, it gives insight on our decision to treat the underlying haematological condition with a BRAF-targeted therapy rather than purine analog-based chemotherapy to reduce the risk of future severe infections.

Coagulase-negative staphylococci release a purine analog that inhibits Staphylococcus aureus virulence

Coagulase-negative staphylococci and Staphylococcus aureus colonize similar niches in mammals and conceivably compete for space and nutrients. Here, we report that a coagulase-negative staphylococcus, Staphylococcus chromogenes ATCC43764, synthesizes and secretes 6-thioguanine (6-TG), a purine analog that suppresses S. aureus growth by inhibiting de novo purine biosynthesis. We identify a 6-TG biosynthetic gene cluster in S. chromogenes and other coagulase-negative staphylococci including S. epidermidis, S. pseudintermedius and S. capitis. Recombinant S. aureus strains harbouring this operon produce 6-TG and, when used in subcutaneous co-infections in mice with virulent S. aureus USA300, protect the host from necrotic lesion formation. Used prophylactically, 6-TG reduces necrotic skin lesions in mice infected with USA300, and this effect is mediated by abrogation of toxin production. RNAseq analyses reveal that 6-TG downregulates expression of genes coding for purine biosynthesis, the accessory gene regulator (agr) and ribosomal proteins in S. aureus, providing an explanation for its effect on toxin production.

Antithymocyte globulin administration in patients with profound lymphopenia receiving a PBSC purine analog/busulfan-based conditioning regimen allograft

Graft-versus host disease (GVHD) remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (ASCT). Prophylactic T cell depletion via antithymocyte globulin (ATG) during ASCT conditioning is one of the standards of care for GVHD prophylaxis, although the optimal dosing strategy is still unclear. Recent studies have reported that absolute lymphocyte count at the time of ATG administration could predict survivals in ASCT from unrelated donors. Here this issue was examined in 116 patients receiving peripheral blood stem cells (PBSC) ASCT with purine analog/busulfan-based conditioning regimens between 2009 and 2019 in our department. The impact of lymphopenia at the time of ATG administration was evaluated in terms of overall survival, disease-free survival and GVHD-free/relapse-free survival. After a median follow-up of 4 years, no adverse effect of a profound lymphopenia was observed on patients’ outcome. Notably, a reduced dose of ATG in patients with profound lymphopenia did not translate into better survivals. This study indicates that ATG can be administered whatever the recipient’s lymphocyte counts in patients receiving a PBSC purine analog/busulfan-based conditioning regimen ASCT.

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia

PURPOSE Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined. PATIENTS AND METHODS Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m2 begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry. RESULTS Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% ( P = .11), MRD-free CR rates 97% versus 24% ( P < .0001, primary end point), and blood MRD-free rates 100% versus 50% ( P < .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; P = .0034) and durability ( P = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% v 9%; P < .0001) and platelet transfusions without bleeding (35% v 0%; P = .0002), but higher neutrophil ( P = .017) and platelet ( P = .0015) counts at 4 weeks. CONCLUSION Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.

Long Term Follow-up of a Phase II Study of Cladribine with Concurrent Rituximab in Patients with Hairy Cell Leukemia Variant

Background Hairy cell leukemia (HCL) variant (HCLv) is considered a separate, more aggressive entity compared to classic HCL. HCLv responds poorly to single-agent purine analog with complete response (CR) rates below 10% and overall response rates under 50%. Rituximab combined with purine-analog can improve response rate and duration, but long-term data have not been reported for HCLv, particularly regarding minimal residual disease (MRD). We therefore update the results of a phase II trial with cladribine and concurrent rituximab in patients with HCLv, previously reported for 10 of the 20 patients enrolled. Methods Patients with HCLv with 0 to 1 prior courses of cladribine, and/or 0-1 prior courses of rituximab, received cladribine (0.15 mg/kg days 1-5), with 8 weekly doses of rituximab (375 mg/m2) beginning day 1. The primary endpoint was to determine CR rate and secondary endpoints included evaluating minimal residual disease (MRD) by blood and bone marrow aspirate flow cytometry, and bone marrow biopsy immunohistochemistry. Patients were able to receive a 2nd course of rituximab ≥ 6 months after the first, if and when MRD was detected in blood. Results Twenty patients were enrolled. Median age was 67 (range: 42-86) years. No patients had prior concurrent cladribine-rituximab. Eight were previously untreated, 1 had only splenectomy, 6 had prior cladribine, 1 had prior cladribine and splenectomy, 1 had prior rituximab, 1 had prior rituximab and splenectomy, 1 had cladribine, rituximab, and splenectomy, and 1 had combination rituximab-containing chemotherapy followed by cladribine. Out of 20 patients receiving concurrent cladribine-rituximab (CDAR), the CR rate was 95% (95% CI: 75-100%). This CR rate was superior to a historical control group of 3 of 39 HCLv patients who achieved CR to cladribine alone (p&lt;0.0001). Sixteen (80%, 95% CI: 56-94%) of 20 patients became MRD-free at 6 months; median duration of MRD-free CR was 72.0 months, with 9 of 16 still MRD-free at 5-108 (median 29.1) months. With median potential follow up of 88 months (range: 7-123 months), 10 patients received delayed rituximab and 4 re-achieved MRD-free CR. Six patients required alternative treatment and 6 patients died, 5 with HCLv including 1 with HCLv limiting treatment for lung cancer, and 1 with Parkinson's disease but still MRD-free. Time from progression of HCLv to death was 5.9-30.0 (median 28.1) months. Achieving MRD-free CR by 6 months after CDAR (16 vs 4 patients) was important for median progression free survival [PFS, unreached vs 17.4 mo, hazard ratio (HR) 0.031, 95% CI 0.003-0.29, p&lt;0.0001] and overall survival (OS, unreached vs 38.2 months, HR infinite since all 4 MRD+ deaths were prior to deaths of 2 patients who achieved MRD-free CR, p&lt;0.0001). A significant relationship between prior purine analog therapy or unmutated IGHV4-34 (n=7) status and either PFS or OS has not yet been observed. Conclusion Concurrent cladribine with rituximab is highly effective in HCLv irrespective of prior purine-analog treatment or IGHV4-34 status and should replace purine analog monotherapy as treatment. Patients with long-term MRD-free CR are being followed to determine whether concurrent cladribine-rituximab as 1st-3rd line systemic therapy can permanently eradicate HCLv. Patients who progress have limited OS. This provides a rationale for the testing of higher intensity approaches up front and the identification of additional treatment options for HCLv. Disclosures Kreitman: Genentech: Research Funding. OffLabel Disclosure: Rituximab for hairy cell leukemia

High Risk of Infections in Chronic Lymphocytic Leukemia Patients Treated with B-Cell Receptor Inhibitors

Introduction: Infection is a major source of morbidity and mortality in CLL. Improved treatment efficacy and decreased immune toxicity of treatment could have altered the spectrum and consequences of infections in patients with CLL. A better understanding of infections complicating the course of non-selected patients with CLL could be useful in improving medical management. Methods: Demographic and clinical information was retrospectively extracted from medical records for clinic visits between May 1st, 2000 and May 1st, 2016 for all patients enrolled in the Wilmot Cancer Institute (WCI) CLL database. Data collected on incident infections included site, etiology, treatment, and setting of care. Major infections were defined as requiring either an inpatient stay or IV antimicrobial treatment. Minor infections were defined as any infectious episode requiring oral antimicrobials and outpatient treatment. Incidence rate ratios (IRR) were generated using Poisson regression to compare infection rates across treatment categories. Results: Two hundred and seventy-five CLL patients contributed 937.7 person-years (p-yrs) of follow up from their first clinic visit at WCI (median follow up 2.1 yrs). Median age at diagnosis was 61.6 and only 8.2% of patients had advanced stage CLL. Most patients were CD38 negative (64.7%), ZAP70 negative (54.6%), and IGHV mutated (51.2%, n=89) and 75.1% had either 13q14 deletion as the only defect or no abnormality on FISH analysis. Sixty percent of patients needed treatment for progressive CLL; among those treated, 50.9% were ever treated with either a purine analog or alemtuzumab, 30.4% were treated with other chemotherapies, and 18.6% had non-chemotherapy treatment. B-cell receptor inhibitor (BCR) therapy was used in sixty-seven patients (63 ibrutinib, 4 idelalisib) and was the only therapy in 18 of them (BCR only). Thirty percent of patients experienced at least one major infection (incidence rate 20.4 per 100 p-yrs) and 62.9% experienced at least one minor infection (69.3 per 100 p-yrs). The most common sites of major infections were the lower respiratory tract (7.8 per 100 p-yrs), skin (2.6 per 100 p-yrs), and urogenital tract (2.0 per 100 p-yrs). Minor infections most commonly affected the upper respiratory tract (26.8 per 100 p-yrs), skin (11.0 per 100 p-yrs, including shingles: incidence rate of 2.8 per 100 p-yrs), and bronchi (9.3 per 100 p-yrs). Patients treated for CLL had a higher risk of major infections (IRR 4.15, 95%CI 2.53, 6.80) and minor infections (IRR 1.48, 95%CI 1.23, 1.79) compared to those never treated. The age and gender adjusted risk of both major and minor infections were significantly increased by treatment with a purine analog or alemtuzumab (Table 1). The risk of major infection in the BCR only group was significantly higher than treatment-naive patients (IRR 3.31 95%CI 1.13, 9.80) and was 43% lower compared to patients treated with other modalities (IRR 0.57, 95%CI 0.21,1.55). The BCR group had a significantly higher risk of a minor infection compared to untreated patients (IRR 1.86 95% 1.14, 3.04), but had a slightly lower risk compared to those treated with other modalities (IRR 0.93 95%CI 0.57, 1.48). The BCR only group had a longer infection free survival compared to those on BCR inhibitor salvage therapy (Figure 1). An intra-patient comparison of infection risk for patients receiving BCR inhibitor salvage therapy compared to their previous chemoimmunotherapy showed an 33% increase in the risk of a major infection (IRR 1.33 95%CI 0.96, 1.86) and a 185% increased risk of a minor infection (IRR 2.85 95%CI 1.57, 5.18). Conclusion: CLL is complicated by a large number of infections, especially in patients with progressive disease who require treatment. Minor infections contribute to considerable disease burden and can have serious sequelae (e.g. post herpetic neuralgia). Given their decreased immune toxicity profile, BCR inhibitors may decrease the risk of infections; however, this has not yet been confirmed. Our sample of CLL patients treated solely with BCR inhibitors experienced higher rates of infection compared to untreated patients. Additionally, patients treated with BCR inhibitors as salvage therapy still experienced higher rates of infection compared to their time on chemoimmunotherapy. Therefore, patients treated with BCR inhibitors should be carefully monitored for infections that can cause significant morbidity or mortality. Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.