EHA Library - The official digital education library of European Hematology Association (EHA)

CD38: A FUNCTIONING TARGET IN RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA. LIMITATIONS IN TREATMENT AND DIAGNOSTICS.
Author(s): ,
Barbora Vakrmanova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Michaela Novakova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Petr Riha
Affiliations:
Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Rep. Ceca;Depart
,
Marketa Zaliova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Eva Fronkova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Ester Mejstrikova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Leona Reznickova Rezkova
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
,
Jan Stary
Affiliations:
Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Rep. Ceca;Depart
,
Ondrej Hrusak
Affiliations:
Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,CLIP, Second Faculty of Medicine and Motol University Hospital,Pragu
Lucie Sramkova
Affiliations:
Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tchèque, République;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Tschechische Republik;Department of Paediatric Haematology and Oncology,Second Faculty of Medicine and Motol University Hospital,Prague,Rep. Ceca;Depart
(Abstract release date: 05/12/22) EHA Library. Vakrmanova B. 06/10/22; 357239; P376
Mrs. Barbora Vakrmanova
Mrs. Barbora Vakrmanova
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P376

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The prognosis of relapsed T-acute lymphoblastic leukemia (ALL) is dismal and there is a need for new treatment options. Daratumumab, a monoclonal kappa chain antibody against CD38 is routinely used in multiple myeloma treatment. CD38 is also expressed in malignant cells of most cases with pediatric ALL.  Accordingly, daratumumab can be used experimentally in treatment of relapsed ALL but data about efficacy of such a treatment is limited. The loss of CD38 described in myeloma patients can be one of the reasons of treatment failure.

Aims

Does daratumumab provide a benefit in relapsed ALL?

Can we observe the inability of anti-CD38 mAbs to bind to leukemia cells after daratumumab treatment as described in myeloma patients?

Methods

We treated five patients with relapsed ALL with daratumumab between 10/2019 – 10/2021 (four of them for a first relapse of T-ALL and one for a second CD19neg relapse of B cell precursor (BCP) ALL). In three patients, daratumumab was used in combination with chemotherapy, in one patient, chemotherapy was early discontinued for toxicity and the remaining patient received it in monotherapy due to clinical condition. Blast positivity of CD38 by a diagnostic monoclonal antibody (mAb) at relapse was confirmed in all patients before treatment started.

Results

Three of five patients responded to daratumumab plus chemotherapy and were in second complete remission (CR2) and underwent stem cell transplantation (SCT). CD38 expression on blasts after daratumumab was not evaluated due to blast elimination in these cases. Two of these patients relapsed with CD38pos ALL 5 and 7 months after SCT, respectively. Third patient is in CR2 one year after SCT. In two of five patients (one with T-ALL and one with a CD19neg BCP ALL) blasts were still detected by flow cytometry after daratumumab. In patient 4 disease progressed under daratumumab treatment. Under the progressing disease patient died 52 days after the relapse. In the other patient, the amount of blasts decreased by one log after the first course of treatment. Nevertheless, the blasts remained on the same log level. Therefore, daratumumab treatment was stopped and replaced by inotuzumab and subsequent SCT, which led to a molecular CR3. We could not detect binding of a diagnostic anti-CD38 (clone T16, HIT2) in neither of the two cases early after the start of daratumumab treatment. We then tested whether the lack of anti-CD38 binding could be caused by steric hindrance with daratumumab molecules as had been described in myeloma patients. We proved our patients had blasts CD38 positive on mRNA level and intracellularly (patient 4). We also detected daratumumab directly on the blasts by detecting its kappa chain on the blasts (patients 4). Moreover, adding daratumumab to blasts of a patient freshly diagnosed with CD38pos BCP ALL blocked anti-CD38 antibody (clone T16) binding. Collectively, the data showed that like in myeloma, daratumumab may block binding of some diagnostic antibodies. We are currently testing the feasibility of multiepitope CYT-38F2 antibody in children with ALL on daratumumab treatment.

Conclusion

In conclusion, daratumumab can lead to CR2 in relapse/refractory ALL, however, the effect is often temporary. Daratumumab administration may result in weeks lasting inability of anti-CD38 mAbs to bind to leukemia cells.

Supported by Ministry of Health of the Czech Republic, grants nr. NU20-03-00284 and NU20J-07-00028.

Keyword(s):

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P376

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The prognosis of relapsed T-acute lymphoblastic leukemia (ALL) is dismal and there is a need for new treatment options. Daratumumab, a monoclonal kappa chain antibody against CD38 is routinely used in multiple myeloma treatment. CD38 is also expressed in malignant cells of most cases with pediatric ALL.  Accordingly, daratumumab can be used experimentally in treatment of relapsed ALL but data about efficacy of such a treatment is limited. The loss of CD38 described in myeloma patients can be one of the reasons of treatment failure.

Aims

Does daratumumab provide a benefit in relapsed ALL?

Can we observe the inability of anti-CD38 mAbs to bind to leukemia cells after daratumumab treatment as described in myeloma patients?

Methods

We treated five patients with relapsed ALL with daratumumab between 10/2019 – 10/2021 (four of them for a first relapse of T-ALL and one for a second CD19neg relapse of B cell precursor (BCP) ALL). In three patients, daratumumab was used in combination with chemotherapy, in one patient, chemotherapy was early discontinued for toxicity and the remaining patient received it in monotherapy due to clinical condition. Blast positivity of CD38 by a diagnostic monoclonal antibody (mAb) at relapse was confirmed in all patients before treatment started.

Results

Three of five patients responded to daratumumab plus chemotherapy and were in second complete remission (CR2) and underwent stem cell transplantation (SCT). CD38 expression on blasts after daratumumab was not evaluated due to blast elimination in these cases. Two of these patients relapsed with CD38pos ALL 5 and 7 months after SCT, respectively. Third patient is in CR2 one year after SCT. In two of five patients (one with T-ALL and one with a CD19neg BCP ALL) blasts were still detected by flow cytometry after daratumumab. In patient 4 disease progressed under daratumumab treatment. Under the progressing disease patient died 52 days after the relapse. In the other patient, the amount of blasts decreased by one log after the first course of treatment. Nevertheless, the blasts remained on the same log level. Therefore, daratumumab treatment was stopped and replaced by inotuzumab and subsequent SCT, which led to a molecular CR3. We could not detect binding of a diagnostic anti-CD38 (clone T16, HIT2) in neither of the two cases early after the start of daratumumab treatment. We then tested whether the lack of anti-CD38 binding could be caused by steric hindrance with daratumumab molecules as had been described in myeloma patients. We proved our patients had blasts CD38 positive on mRNA level and intracellularly (patient 4). We also detected daratumumab directly on the blasts by detecting its kappa chain on the blasts (patients 4). Moreover, adding daratumumab to blasts of a patient freshly diagnosed with CD38pos BCP ALL blocked anti-CD38 antibody (clone T16) binding. Collectively, the data showed that like in myeloma, daratumumab may block binding of some diagnostic antibodies. We are currently testing the feasibility of multiepitope CYT-38F2 antibody in children with ALL on daratumumab treatment.

Conclusion

In conclusion, daratumumab can lead to CR2 in relapse/refractory ALL, however, the effect is often temporary. Daratumumab administration may result in weeks lasting inability of anti-CD38 mAbs to bind to leukemia cells.

Supported by Ministry of Health of the Czech Republic, grants nr. NU20-03-00284 and NU20J-07-00028.

Keyword(s):

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies