Since the inaugurational meeting in 1981, the International Conference on Malignant Lymphoma (ICML), traditionally takes place in Lugano, Switzerland, has become one of the ‘must-attend events’ for anyone involved in the study and treatment of lymphoid neoplasms.

Organized once every two years,in collaboration with the American Association for Cancer Research (AACR), the meeting offers hematologists, clinical oncologists, radio-oncologists, pediatricians, pathologists and leading researchers in the field a great opportunity to to present and discuss the most recent basic and clinical data on a specific morphologic subtype or on a pathways or other biological aspect. Translational and/or pathological aspects are also discussed.

This year a large number of high-quality presentations included the latest updated about Antibody-drug Conjugates.

A New Role for CD37
AGS67E (Astellas Pharma/Agensys) is an antibody-drug conjugate targeting CD37, a tetraspanin expressed on malignant B cells, which includes a fully human monoclonal IgG2 antibody (AGS67C) conjugated to the cytotoxic, microtubule-disrupting, payload monomethyl auristatin E (MMAE) which is linked to reduced cysteines of the antibody via a protease-cleavable linker (maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamoyl). The trial drug is being investigated in patients with relapsed/refractory non-Hodgkin Lymphoma (NHL) in a phase I dose-escalation study.

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The data presented this year at the International Conference on Malignant Lymphoma demonstrates a high level of CD37 detection of ≥80% in NHL, including diffuse large B-cell lymphomas (DBCL), making it a potential drug target. But the results also suggest that AGS67E may serve as a potential therapeutic for B-cell malignancies [1][2]

ADCT-301 and ADCT-402
ADCT-301 (ADC Therapeutics), an antibody drug conjugate comprising a human monoclonal antibody against CD25 conjugated to a potent pyrrolobenzodiazepine dimer toxin,  has demonstrated potent anti-tumor activity in pre-clinical studies against CD25-expressing hematological malignancies. Interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, included in a poster, confirm that the investigational agent was well tolerated with manageable toxicities. [3]

Interim results from the Phase I, open label, dose-escalating study of ADCT- 402 (ADC Therapeutics), targeting CD19, evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory non- Hodgkin’s lymphoma (r/r NHL) confirm efficacy and tolerability of ADCT-402. [4]

STRO-001 is a novel CD74-targeting antibody-drug conjugate based on Sutro’s lead human IgG1 antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-payload with an average drug-antibody ratios (DAR) of 2. The investigational agent, which demonstrates potent in vitro cytotoxicity in NHL cell lines and anti-tumor activity in NHL xenograft models, was developed using  precise site-specific conjugation enabled by Sutro’s cell-free antibody synthesis technology. Study results presented at 14th-ICML confirm potent anti-tumor activity in diffuse large B-cell lymphoma and mantle cell lymphoma tumor models while reducing the potential for toxic secondary effects on adjacent healthy cells. clinical studies of this novel ADC for treatment of B-cell malignancies are under development. [5]

Polatuzumab vedotin
Results from a multicenter, open-label, dose-escalation study evaluating the safety and anti-tumor activity of polatuzumab vedotin (DCDS4501A or RG-7596; Genentech/Roche) in combination with rituximab or obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) in patients with non-Hodgkin’s lymphoma, were presented at 14th-ICML.

CD79b is a signaling component of the B-cell receptor or BCR restricted to the B-cell lineage. In a study published in 2009, Droman et al reported the detection of surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients.  Based on this finding, these researchers concluded that anti-CD79b-vcMMAE could be widely used in these malignancies. [6]

The researchers concluded that a combination of  polatuzumab vedotin at 1.8 mg/kg with R-CHP has an acceptable safety profile and produced promising response rates at the end of treatment, warranting further exploration the investigational drug. [7]

A separate presentation showing updated evaluation of polatuzumab vedotin + bendamustine to polatuzumab vedotinrituximab and substituting obinutuzumab for rituximab shows promising durable responses and an acceptable safety profile in heavily pre-treated transplant ineligible patients with relapsed/refractory (R/R) Follicular or Diffuse Large B-Cell Lymphoma, which generally have poor treatment outcomes.[8]

Brentuximab Vedotin
The complete remission (CR) rate of Hodgkin lymphoma after first line treatment is generally between 80% and 90%. However, about 10% of these patients are refractory and 10% to 30% relapse after achieving a complete remission. The standard of care for suitable patients with relapsed/refractory Hodgkin lymphoma includes high dose chemotherapy followed by autologous stem cell transplant or ASCT.  But patients who relapse after ASCT have a dismal prognosis.

New treatment options including the anti-CD30 antibody-drug conjugate brentuximab vedotin (Adcetris®; Seattle Genetics) are associated with an overall response rate or ORR of 75% and CR rate of 34%.  Results presented during the 14th-ICML report results from a study in which researchers evaluated toxicity, efficacy, and duration of response (DOR) of a combination of brentuximab vedotin and bendamustine, which has demonstrated efficacy in several lymphoproliferative disorders.

The data showed a high response rate (87% ORR and 54% CR) with the combination of brentuximab vedotin and bendamustine, showing a PFS of 80% at 12 months. The median DOR of the CR remission group was 14 months, highlighting durable responses.

The combination of brentuximab vedotin and bendamustine has shown an acceptable toxic profile with only 1 grade 4 adverse event and was able to be delivered as an outpatient regimen. The researchers concluded that the combination is a promising salvage treatment for heavily pretreated patients with R/R Hodgkin lymphoma. They conclude that large investigational trials are necessary to warrant these initial results. [9]

Diagram 1.0: Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma (NCT01492088)

Trial results from a separate trial confirm that high-dose bendamustine plus brentuximab has shown relevant efficacy and a relatively good safety profile in a setting of heavily pretreated patients with Hodgkin lymphoma.  The combination could be considered as a bridge to second autologous or allogenic stem cell transplant.[10]

In an unrelated study, brentuximab vedotin showed clinically meaningful response rates in patients with this R/R Hodgkin lymphoma and Systemic Anaplastic Large-Cell Lymphoma (sALCL). In this study, 47% of patients proceeded to transplant.

The results of the study show that brentuximab vedotin is a feasible treatment option in pediatric Hodgkin lymphoma and Systemic Anaplastic Large-Cell Lymphoma that can facilitate relapsed patients proceeding to transplant. [11]

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