Autologous Stem Cell Transplantation after Conditioning with Chidamide Plus Carmustine, Etoposide, Cytarabine, and Cyclophosphamide (Chi-BEAC) for Treatment of High-Risk and Relapsed/Refractory Aggressive Lymphoma: Multi-Center, Single-Arm, Open-Label Phase II Clinical Trial

Background: Chidamide, as a novel subtype-selective histone deacetylase inhibitors (HDACi), can directly inhibit tumor cell cycle progression and induce tumor cell apoptosis, inhibit phenotypic transformation of tumor cells and pro-drug resistance/pro-metastasis activity of the microenvironment, induce differentiation of tumor stem cells, and reverse epithelial-mesenchymal transformation of tumor cells, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and enhancing the effect of chemotherapy agents through loosening chromatin and exposing DNA. The efficacy and safety of chidamide-BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide, Chi-BEAC) conditioning regimen combined with autologous stem cell transplantation (ASCT) were evaluated in a current phase II clinical trial for the treatment of high-risk and relapsed/refractory aggressive lymphoma. Methods: A total of 70 patients with high-risk diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) who had achieved complete remission (CR) or partial remission (PR) after first-line therapy or second-/third-line therapy were recruited from January 2018 to June 2021. Three of the patients were not evaluated after ASCT and two patients withdrew from the study; 65 patients were then evaluated for the effectiveness of Chi-BEAC treatment. Results: DLBCL and MCL are referred as B-cell non-Hodgkin lymphoma (B-NHL) and PTCL is referred as T and NK-cell non-Hodgkin lymphoma (T&NK-NHL) in the study. The median neutrophil engraftment time was 10 d (7-13 d) and median platelet engraftment time was 11 d (8-13 d). The CR rate at 3-6 months after transplantation was 75.4% in the 65 evaluable patients. The median progression free survival (PFS) and overall survival (OS) had not reached at the end of the follow-up period (median 18.1 month; range 1.8-42.0 months). The estimated PFS and OS at 24 months was 78.5% and 84.2%, respectively. Stratified analyses showed that in patients with B-NHL who previously received first-line treatment, the CR rate at 3-6 months after transplantation was 77.8%, and 2-year PFS was 74.8%. The survival rate might be better than previously reported for SWOG9704 (Stiff et al., 2013; PMID 24171516)-a 2-year PFS of 69%-and for DLCL04 (Chiappella et al., 2017; PMID 28668386)-a 2-year failure-free survival of 71%. In our patients with B-NHL who previously received second-/third-line treatments, the CR rate at 3-6 months after transplantation was 71.4%, and 2-year PFS was 77.1%. The survival rate might also be higher than previously reported for the CORAL trial (Gisselbrecht et al., 2010; PMID: 20660832), which showed a 2-year PFS of approximately 65%. In our patients with T&NK-NHL the CR rate at 3-6 months after transplantation was 73.3%, and 2-year PFS was 93.3%, The survival rate might be higher than previously reported for the NLG-T-01 trial (Francesco d'Amore et al., 2012; PMID: 22851556), which showed a 2-year PFS of approximately 55%. PFS stratification analysis showed that previous treatment outcomes affected the PFS: patients who had achieved CR before transplantation demonstrated better PFS than patients who had achieved PR (P = 0.199), while there was no significant difference between patients with different pathological subtypes (B or T&NK-NHL) or different risk groups. Most non-hematological adverse events (AEs) were of grade 1/2. Grade 4 AE only occurred in one patient, i.e., γ-glutamyl transpeptidase (GGT) elevation. Grade 3 AEs that occurred in ≥ 5% of the patients included febrile agranulocytosis (37.7%), hypokalemia (24.7%), hyponatremia (23.4%), GGT elevation (9.1%), and diarrhea (5.2%), which were well tolerated. Conclusions: This study showed that inclusion of the HDACi chidamide in conditioning regimen for ASCT greatly increased the PFS and OS, especially in patients with T&NK-NHL, and revealed an acceptable safety profile for refractory and relapsed lymphoma patients. Therefore, chidamide-containing conditioning regimen may be a great choice for patients with refractory and relapsed lymphoma, and awaits further confirmation by additional large-scale multi-center investigations. Disclosures No relevant conflicts of interest to declare.

Case Report: Refractory Cryptosporidiosis after CAR T-Cell Therapy for Lymphoma

Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post–chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non–HIV-infected immunosuppressed host.

Acute Hemolytic Transfusion Reaction Due to Pooled Platelets: A Rare but Serious Adverse Event

A female patient aged 65 years with blood group A with relapsed lymphoma had thrombocytopenia; leukocyte-reduced group O prestorage pooled platelet concentrates (PPLTs) were transfused without adverse events. She was discharged home, but 1.5 hours later she returned with fever and dark urine. Hypotension and tachycardia developed; she was admitted to the intensive care unit. Post-transfusion blood and urine samples were obtained. Serial dilutions from 5 donor testing tubes and a simulated PLT pool were performed and read at immediate spin and IgG. Testing confirmed an acute hemolytic transfusion reaction (AHTR): elevated lactate dehydrogenase (996 U/L; normal range 135 U/L–225 U/L) and undetectable haptoglobin (<10 mg/dL; normal range 30 mg/dL–200 mg/dL) levels. Urinalysis showed dark amber urine but no significant quantity of red blood cells. At 37ºC the simulated pool and donor number 5 had high-titer anti-A. As a precaution, the donor was permanently deferred. Research has shown that PLT-associated AHTR has occurred with apheresis platelets but is very rare with whole blood–derived PLTs.

Ruxolitinib for the treatment of lymphoma-associated hemophagocytic lymphohistiocytosis: A cautionary tale

Introduction Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome characterized by fever, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and pancytopenia. Three publications reported success with ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor. This therapy interrupts the production of cytokines associated with hemophagocytic lymphohistiocytosis, namely interferon-γ and interleukins 2, 6, and 10. Case report We administered ruxolitinib to two patients with lymphoma-associated hemophagocytic lymphohistiocytosis who had failed standard treatment with dexamethasone and etoposide. Management and outcome Patient #1 was started on ruxolitinib 10 mg BID, and titrated to 15 mg BID. All but two of the hemophagocytic lymphohistiocytosis criteria resolved within two weeks, and she was able to restart therapy for lymphoma. During her ruxolitinib taper, she again presented with relapsed hemophagocytic lymphohistiocytosis. She was taking 2.5 mg a day at the time. Despite salvage treatment, she died from the disease. Patient #2 was a diffuse large B-cell lymphoma patient who presented with hemophagocytic lymphohistiocytosis and was treated with chemoimmunotherapy and achieved a complete response (CR). Hemophagocytic lymphohistiocytosis symptoms relapsed, and he was treated with ruxolitinib. He developed relapsed lymphoma and unfortunately died. Discussion While treating the underlying lymphoma is a clear priority, the cytopenias and other symptoms of hemophagocytic lymphohistiocytosis complicate the delivery of this therapy. Hence, the use of ruxolitinib as a bridge to definitive therapy was appealing. However, we are concerned about the progression of lymphoma while these patients were taking ruxolitinib. Ruxolitinib may be controlling cytokine storm associated with hemophagocytic lymphohistiocytosis, while other aspects of the condition are progressing. Therefore, we would advise caution in its use in lymphoma-associated-hemophagocytic lymphohistiocytosis until more data are available.

The Advances and Challenges of CAR-NK Cells for Tumor Immunotherapy

Immunotherapies using chimeric antigen receptor (CAR)-T cells bring an encouraging vision to non-Hodgkin lymphoma patients who develop relapsed lymphoma or are unresponsive to standard chemotherapy, yet they also have limitations and drawbacks. Clinical trials have reported cases of neurotoxicity and cytokine release syndrome (CRS) accompanied by CAR-T cell therapies. To establish a more mature therapy, CAR incorporated into Natural Killer (NK) cells came into being. As a leukocyte involved in innate immunity, NK cell does not require MHC matching, making the production of allogeneic “off-the-shelf” CAR-NK cells possible. Moreover, the controllable life span of CAR-NK cells and little risk of graft-versus-host disease reduce side effects companion by CAR-T. This review provides an overview of CAR-NK design and production before delivery to patients. Different sources of NK cells are compared and the development of CAR molecule construction is introduced.

Combination of Bleomycin and Cytosine Arabinoside Chemotherapy for Relapsed Canine Lymphoma

ABSTRACT A retrospective study was performed to evaluate response rate, time to progression, and toxicity of a bleomycin and cytosine arabinoside (Bleo/Cytarabine) combination protocol for dogs with relapsed lymphoma (LSA). Dogs diagnosed with LSA and previously treated with chemotherapy were included in the study. A total of 20 dogs met the inclusion criteria, and 19 were evaluable for response. Bleomycin was administered subcutaneously on days 1 and 8 and cytosine arabinoside was administered subcutaneously on days 1–5 of a 21-day cycle. The median number of chemotherapy drugs given prior to the administration of Bleo/Cytarabine was 8.5. A total of 23 cycles of Bleo/Cytarabine were administered. The overall response rate was 36.8% (7 of 19 dogs had a partial response). The median time to progression was 15 days. Three dogs developed grade 3 thrombocytopenia and one dog had a grade 4 neutropenia. Bleo/Cytarabine had minor activity when used as a rescue therapy for pretreated LSA patients.