<scp>CD</scp>38‐negative relapse in multiple myeloma after daratumumab‐based chemotherapy

Minařík, Jiří; Novák, Martin; Flodr, Patrik; Balcárková, Jana; Mlynarcikova, Miroslava; Krhovská, Petra; Pika, Tomáš; Pikalova, Zuzana; Bačovský, Jaroslav; Scudla, Vlastimil

doi:10.1111/ejh.12902

Cited by 24 publications

(14 citation statements)

References 17 publications

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“…Our results show that the effect of DARA in MM is indisputable. Several issues are still to be resolved including the long-term outcomes when DARA is used in earlier treatment lines, the unexpectedly good synergy of DARA and lenalidomide or possible down-regulation of CD38 and the occurrence of CD38-negative relapses after DARA as reported in our previous paper 18 .…”

Section: Discussionmentioning

confidence: 86%

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

Minařík

Pour

Maisnar

et al. 2019

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Objective. The treatment of relapsed and refractory multiple myeloma (RRMM) remains challenging. The outcomes in highly pretreated populations are unsatisfactory and there is urgent need for novel and safe therapeutic approaches. Recently, daratumumab has been approved for RRMM with promising results even in monotherapy. The aim of this study was to assess the efficacy of single agent daratumumab outside a clinical trial. Patients and Methods. 14 patients with RRMM and significant pretreatment (median 4.5 previous lines) entered a specific healthcare program and received treatment with single agent daratumumab. They were followed for therapeutic response based on IMWG criteria, and incidence of adverse events. The data were collected using the Registry of Monoclonal Gammopathies. Results. The overall response rate was 38.5%. 23.1% of patients reached very good partial response, 15.4% reached partial remission, 15.4% had minimal response, 38.5% had stable disease and 7.7% had progressive disease. The median progression free survival was 4.6 months and median overall survival was not achieved. The toxicities were mostly mild, only infectious complications and hematological toxicity reached grade III. Conclusion. We conclude that daratumumab has significant activity in highly pretreated RRMM even as a single agent, with an acceptable toxicity profile and survival impact.

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Section: Discussionmentioning

confidence: 86%

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

Minařík

Pour

Maisnar

et al. 2019

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Such approaches are very effective against receptors like CD33, which is endocytosed after Ab binding, enabling the cytotoxic payload to internalize and result in cell killing (32,33). Futhermore, after CD33 antibody therapy, blasts in relapsed/refractory disease continue to express CD33, suggesting that AML cells may not use downregulation of CD33 as an epigenetic "escape mechanism" (22), in contrast to the use of anti-CD38 mAb daratumumab which may result in relapse due to a CD38myeloma clone (34). Therefore, CD33 PET imaging would be useful in monitoring treatment response post intervention, including CD33 targeted treatment.…”

Section: Discussionmentioning

confidence: 99%

AML ImmunoPET:⁶⁴Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model

Madabushi

Brooks

Zuro

et al. 2019

Preprint

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provides consulting for Amgen and Stemline and is on the speakers' bureau for the former company. Joseph Rosenthal receives honoraria from and consults for Shire and Bayer, and receives research funding from Daiichi Sankyo and Kite Pharma. All other authors declare no competing financial interests. Abstract: 245 words Translational relevance: 153 words Abstract: Purpose:Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific non-invasive imaging method to assess disease in the whole body, including in extramedullary organs, representing an unmet clinical need. About 85-90% of human myeloid leukemia cells express CD33 (an accepted biomarker for AML) cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET. Experimental Design:In this study, we evaluated if 64 Cu-DOTA-anti-CD33 murine monoclonal antibody (mAb) can be used for ImmunoPET-CT imaging of AML in preclinical model. For translational purpose, a humanized anti-CD33 antibody was produced, and after confirming its anti-CD33 PET-CT imaging ability we further explored its therapeutic potential. Results:64 Cu-DOTA-anti-CD33 based PET-CT imaging detected CD33 + AML in mice with high sensitivity (95.65%) and specificity (100%). In the entire skeletal system, CD33 + PET activity was significantly high in the bones of AML bearing mice over non-leukemic control mice; femur (p<0.00001), tibia (p=0.0001), humerus (p=0.0014), and lumber spine (p<0.00001).Interestingly, the imaging showed CD33 + PET activity prevelant in epiphysis/diaphysis of the bones, indicating spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (p=0.02) and 225 Ac-anti-CD33-RIT (p<0.00001), significantly reduced disease burden over that of respective controls. Conclusion:We have successfully developed a novel anti-CD33 immunoPET-CT based non-invasive imaging tool for diagnosis of AML and its spatial distribution, which indicates a preferential skeletal niche.

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“…Such approaches are very effective against receptors like CD33, which is endocytosed after Ab binding, enabling the cytotoxic payload to internalize and result in cell killing (31,32). Furthermore, after CD33 antibody therapy, blasts in relapsed/refractory disease continue to express CD33, suggesting that AML cells may not use downregulation of CD33 as an epigenetic "escape mechanism" (24), in contrast to the use of anti-CD38 mAb daratumumab which may result in relapse due to a CD38 À myeloma clone (33). Anti-CD33 mAb has been clinically validated as an ADC (34)(35)(36) and for RIT (37)(38)(39)40).…”

Section: Discussionmentioning

confidence: 99%

ImmunoPET, [64Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model

Madabushi

Brooks

Zuro

et al. 2019

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.Experimental Design: We evaluated whether [ 64 Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibodyspecific targeting with an antibody-drug conjugate (ADC) and radioimmunotherapy (RIT). Results:[ 64 Cu]Cu-DOTA-anti-CD33-based PET-CT imaging detected CD33 þ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33 þ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P ¼ 0.0001), humerus (P ¼ 0.0014), and lumber spine (P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (P ¼ 0.02) and [ 225 Ac]Ac-anti-CD33-RIT (P < 0.00001) significantly reduced disease burden over that of respective controls.Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT-based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.

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CD38‐negative relapse in multiple myeloma after daratumumab‐based chemotherapy

Cited by 24 publications

References 17 publications

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

AML ImmunoPET:⁶⁴Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model

ImmunoPET, [64Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model

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CD38‐negative relapse in multiple myeloma after daratumumab‐based chemotherapy

Cited by 24 publications

References 17 publications

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population

AML ImmunoPET:64Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model

ImmunoPET, [64Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model

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AML ImmunoPET:⁶⁴Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model