Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure [Phase 1 trial]

Highlights: 

●      Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission.

●      This study evaluated the safety, feasibility and preliminary efficacy of an anti-CD19 enhanced CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity.

●      huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy.

A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell–associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached). 

Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma [Phase 3 clinical trial] 

Highlights: 

●      Combination of acalabrutinib with bendamustine-rituximab significantly improved progression-free survival (PFS).

●      Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Patients aged ≥65 years with previously untreated mantle cell lymphoma (MCL) received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus 6 cycles of  bendamustine (90 mg/m²; days 1 and 2) and rituximab (375 mg/m²; day 1) followed by rituximab maintenance in responding patients for 2 years. In total, 598 patients were randomized, with 299 in each arm. At a median follow-up of 44.9 months, median PFS (primary endpoint) was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.57 to 0.94; P = 0.0160). Benefit was seen across all subgroups, including those with high-risk features. Overall survival was not significantly different (HR, 0.86; 95% CI, 0.65 to 1.13; P = 0.27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

Intrathecal chemotherapy for ciltacabtagene autoleucel-associated movement and neurocognitive toxicity [Case series]

Highlights: 

●      Ciltacabtagene autoleucel (cilta-cel; B-cell maturation antigen [BCMA]-directed chimeric antigen receptor [CAR] T-cell) can rarely lead to persistent movement and neurocognitive toxicities including parkinsonism. 

●      It is a subacute hypokinetic movement disorder emerging approximately 1-2 months after CAR T-cell infusion.

●      The mechanism of cilta-cel-associated parkinsonism is not well-elucidated.

●      Intrathecal (IT) chemotherapy may be a safe and effective treatment for parkinsonism with cerebrospinal fluid (CSF) lymphocytosis while high doses of cyclophosphamide (HD-Cy) may be useful for refractory cases.

The authors analyzed five cases of cilta-cel-associated parkinsonism (8% institutional incidence). The median time to onset of parkinsonism was 26 days (range 9-36).  For parkinsonism-directed therapies, all patients received systemic corticosteroids without effect. IT chemotherapy (‘Triple IT’) was administered to all patients.  For patients with only partial improvement or persistent CSF lymphocytosis, IT thiotepa (10 mg) with hydrocortisone (50 mg) was given (due to its superior anti-myeloma properties in the event of occult disease

driving persistent CSF lymphocytosis). For the two patients without complete resolution to IT chemotherapy, intravenous HD-Cy  was administered. The authors report an 8% institutional incidence of cilta-cel associated parkinsonism and the presence of CSF CAR T-cell pleocytosis as a marker for response to IT chemotherapy.

Peripheral T- and natural killer-cell lymphomas: ESMO–EHA Clinical Practice
Guideline for diagnosis, treatment and follow-up

Here are some recommendations of some subtypes.

Key points: 

1. Diagnosis:

-        If available, positron emission tomography (PET)-computed tomography (CT) at diagnosis, at first restaging (optional) and at end-of-treatment can be considered the preferred imaging modality for all nodal and extranodal (non-leukemic) peripheral T-cell and natural killer (NK)-cell lymphomas (PTCLs).

-        In all cases, a bone marrow biopsy is recommended for accurate staging, including studies of virus expression.

2. First-line treatment: All PTCL patients should, whenever possible, be offered the opportunity to participate in a clinical trial. See Figures 1 to 3 in the original publication.

●      PTCL-NOS and follicular helper T-cell-derived lymphoma (angioimmunoblastic and follicular types and not otherwise specified):  

-        Cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) or CHOP-like chemotherapy (ChT) (e.g. CHOP-etoposide [CHOEP]) can be recommended as first-line therapy.  

-        In patients with limited-stage, non-bulky disease and a favorable pre-therapeutic risk profile, an abbreviated course of ChT (e.g. three to four cycles of CHOP or CHOEP) can be considered.  

-        Consolidative involved-site radiotherapy (ISRT) can be considered for responding patients with limited-stage disease after CHOP or CHOP-like ChT.

-        Consolidative autologous hematopoietic stem cell transplantation (auto-HSCT) can be considered in responding patients with high-risk limited-stage or advanced disease.

●      Anaplastic large-cell lymphoma (ALCL), systemic types:  

-        In patients with limited-stage, non-bulky ALK-positive or ALK-negative disease and a favorable pre-therapeutic risk profile (International Prognostic Index [IPI] 0-1), an abbreviated course of ChT (e.g. three to four cycles of brentuximab vedotin-cyclophosphamide-doxorubicin-prednisolone [BV-CHP] or CHOEP) can be considered.

-        Six cycles of BV-CHP is recommended for all other ChT eligible patients (i.e. both ALK-negative and ALK-positive).

-        Alternatively, six cycles of CHO(E)P can be considered.

-        Consolidative ISRT can be considered for limited-stage ALCL.

-        Consolidative auto-HSCT in first complete remission (CR) can be considered for HSCT-eligible, chemosensitive patients with ALK-negative ALCL.

-        In general, auto-HSCT cannot be recommended for patients with ALK-positive ALCL in first CR. It can, however, be considered for patients with high-risk features (IPI ≥2, bulky disease) with no CR after three cycles of ChT.

●      Epstein–Barr virus (EBV)-associated extranodal NK- or T-cell lymphoma (ENKTCL): 

-        EBV DNA in peripheral blood should be monitored by quantitative PCR at baseline and during therapy as a biomarker of response, in addition to imaging-based response assessment.

-        Fit patients with limited-stage disease should receive ISRT with concurrent, interposed or sequential anthracycline-free, L-asparaginase-containing ChT (e.g. dexamethasone-cisplatin-gemcitabine pegylated L-asparaginase [DDGP] or modified dexamethasone-methotrexate-ifosfamide- pegylated L-asparaginase-etoposide [mSMILE] for HSCT-eligible and L-asparaginase-methotrexate-dexamethasone [AspMetDex] or pegylated L-asparaginase-gemcitabine-oxaliplatin [P-GEMOX] for HSCT-ineligible patients).

-        A multiagent, anthracycline-free, L-asparaginase-containing regimen can be recommended for patients with stage III and IV nasal disease or stage I-IV extranasal disease (e.g. DDGP or mSMILE for HSCT-eligible and AspMetDex or P-GEMOX for HSCT-ineligible patients). Addition of ISRT can be decided on a case-by-case basis.

-        First-line treatment with anti-PD-1 antibodies such as sintilimab (not European Medicines Agency [EMA] or Food and Drug Administration [FDA] approved)  in combination with L-asparaginase-containing regimens (e.g. P-GEMOX) should also be considered in patients with stage III and IV nasal disease or stage I-IV extranasal disease.

-        If available, crisantaspase (Erwinia chrysanthemi-derived L-asparaginase) is recommended for patients who have developed hypersensitivity or inactivating antibodies to Escherichia coli-derived L-asparaginase (not EMA or FDA approved in ENKTCL).

-        In HSCT-eligible responding high-risk patients, consolidative auto- or allogeneic-HSCT can be considered. The choice of HSCT should be made on a case-by-case basis considering factors such as pretherapeutic risk profile, response to first-line therapy, performance status and donor availability.

●      T-cell prolymphocytic leukemia (T-PLL):  

-        A watch-and-wait approach can be recommended for asymptomatic T-PLL.

-        Alemtuzumab is recommended for newly diagnosed symptomatic T-PLL (not EMA or FDA approved but available via named-patient access).

-        Assessment of CD52 status by flow cytometry can be recommended before, during and after treatment.

-        During alemtuzumab therapy, antimicrobial prophylaxis against herpes zoster and Pneumocystis jirovecii are recommended, as well as quantitative cytomegalovirus DNA monitoring.

-        Consolidative non-myeloablative allogeneic-HSCT can be recommended in eligible patients achieving CR who have a donor; otherwise, auto-HSCT can be considered on a case-by-case basis.

Mastocytosis [Review] 

Key points: 

●      Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems.

●      The disease is divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms.

●      Clinical signs and symptoms mostly arise from mast cell mediator effects in the skin, cardiovascular system, gastrointestinal tract and/or bones, leading to flushing, pruritus, hypotension, abdominal pain, diarrhoea, or osteopenia or osteoporosis.

●      Such signs and/or symptoms may also be recorded in smouldering SM and advanced SM. However, in these patients, the clinically relevant findings and symptoms are mostly triggered by mast cell infiltration, leading to organomegaly (hepatomegaly, splenomegaly, lymphadenopathy (B-findings)) or to organ damage (such as cytopenia, malabsorption, portal hypertension or osteolysis (C-findings). B-findings refer to organ involvement without organ failure, while C-findings refer to organ involvement with organ dysfunction.

●      Most patients with mastocytosis present with typical maculopapular skin lesions, formerly also known as urticaria pigmentosa. These skin lesions are present in almost all patients with CM and in >80% patients with SM.

●      Patients without skin lesions are diagnosed with mastocytosis via bone marrow biopsy, which is initiated to clarify on suspected symptoms of mast cell activation on laboratory abnormalities such as changes in blood counts (cytopenias or cytoses) or elevated baseline serum tryptase, or on ‘unexplained’ osteoporosis or sclerotic or lytic bone lesions radiographically resembling multiple myeloma or metastatic disease.

●      The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favorable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor.

●      Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis.

●      For those presenting with atypical symptoms (low score on predictive scoring systems for mastocytosis) and no skin lesions but with elevated serum tryptase, a HαT test (to screen for TPSAB1 gene multiplications) and if negative, a subsequent KIT ^D816V test in peripheral blood leukocytes, may help to reach a decision regarding a referral for bone marrow examinations.

●      The major SM criterion is the formation of compact mast cell clusters and infiltrates (at least 15 mast cells in aggregates) in stained sections of bone marrow or of another extracutaneous organ. See Box 1 and Figure 1 in the complete publication. 

●      KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.

●      Polychemotherapy and hematopoietic stem cell transplantation are usually recommended for patients with advanced SM which is tyrosine kinase inhibitor resistant and who are eligible for intensive therapy.