Skip to main content

Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript

Abstract

Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) has a very poor prognosis with a median overall survival of four to nine months. Achieving a complete molecular response is most often required to obtain a sustained leukemia-free survival after allogeneic hematopoietic stem cell transplantation. Immunotherapies targeting CD19, CD20, or CD22 are very efficient in achieving this goal. However, in the absence of the expression of these immunotherapeutic targets by lymphoblasts, treatment options are extremely scarce. We report the successful treatment of a 26-year-old man who suffered R/R, CD19, CD20, and CD22 negative B-ALL targeting Bcl-2 and CD38 by combining venetoclax and daratumumab with chemotherapy.

To the editor.

Patients with R/R B-ALL have unmet clinical needs [1, 2]. Achieving a complete molecular response is most often required to obtain a sustained leukemia-free survival after allogeneic hematopoietic stem cell transplantation (ASCT). Immunotherapies targeting CD19 or CD22 are very efficient in achieving this goal. However, B-ALL may escape targeted therapies by developing CD19 or CD22 negative blast cells and/or by switching to a mixed myeloid and lymphoid phenotype.

A 26-year-old man presented with asthenia and fever. The white blood cell count was 121 G/l, hemoglobin 65 g/l, and platelets 44 G/l. 95% of bone marrow cellularity was infiltrated by a pro-B ALL that was positive for CD34, HLA-DR, CD19, CD38, TdT, BCL-2, partially CD79a, and negative for CD10, CD123, cytoplasmic IgM and cytoplasmic CD3. Conventional karyotype was normal (46,XY). Polymerase chain reaction (PCR) and fluorescence in situ hybridization detected a KMT2A-AFF1 fusion gene transcript. The ALL was treated according to the GRAALL-2005 induction protocol [3]. A morphologic complete remission (CR) was achieved on Day39. However, minimal residual disease (MRD) was positive with both real-time quantitative PCR of KMT2A-AFF1 fusion transcript (11% of ABL reference gene) and allele specific real-time quantitative PCR of immunoglobulin heavy chain (IGH) gene rearrangement (10-2 relative to the diagnostic sample). Accordingly, the ALL was considered at very high risk and an ASCT was planned. Despite two high dose cytarabine and methotrexate consolidation chemotherapies [3], the response remained insufficient with positive MRD on Day82 (KMT2A-AFF1: 2.67%). Blinatumomab (15 mcg/m2/d) was started as a bridge to ASCT from an HLA-identical sibling donor. Despite 3 cycles of blinatumomab, pre-transplantation MRD, an independent major risk of relapse [4], remained unfavorable (KMT2A-AFF1 0.012% and IGH 10-3). ASCT was performed on Day203 after a myeloablative conditioning (total body irradiation, cyclophosphamide, and etoposide) without T-cell depletion. Post-transplant MRD was undetectable for a year. Unfortunately, MRD became positive at Day582 (IGH 7 × 10-4) (Fig. 1). Despite one cycle of blinatumomab followed by donor lymphocyte infusion (DLI), MRD progressively increased, without additional genetic mutations. The B-ALL escaped the blinatumomab monotherapy following the loss of CD19 expression by lymphoblasts (Fig. 2.1). Despite FLAG-Ida salvage therapy, and two additional DLIs, ALL relapsed 5 months later (IgH MRD: 7 × 10-1 and KMT2A-AFF1 40.6% on Day826; DNA microarray identified the deletion of 11q23.3q23.3 involving KMT2A gene with a frequency of 80% and KMT2A rearrangement was detected by FISH at the frequency of 47%). At that time, the blast cell immunophenotype was as follow: CD19-, CD200+, CD10-, CD20-, CD38+, CD22-, CD81+, CD34+, CD117-.

Fig. 1
figure 1

Minimal Residual Disease measured by real-time quantitative PCR: allele specific of immunoglobulin heavy chain (IGH) gene rearrangement (two distinct markers) and (below) : KMT2A/AFF1 fusion transcript (% of ABL reference gene). CDVPA : cyclophosphamide, daunorubicin, vincristine, prednisone, asparaginase.

In the absence of CD19, CD20, and CD22 expression by lymphoblasts, treatment options were scarce in this young adult with ECOG 0 performance status. During stem cell donor search, the patient received clofarabine 20 mg/m2/d and cytarabine 1000 mg/m2/d for 5 days with venetoclax 400 mg/d (Day1-13), as blasts expressed BCL-2 (Fig. 2.2) and as venetoclax efficacy was reported in pediatric B-ALL models with MLL rearrangements [5, 6]. At Day28, morphologic CR was achieved; however, MRD remained positive (IgH: 10−3; KMT2A-AFF1: 0.15%).

Fig. 2
figure 2

1) Flow cytometry analysis on Day0 showing blasts cells, gated on CD45/side scatter display, are positive for CD19 and CD38 and negative for CD20 and CD22. On Day826, at relapse and after the exposure to blinatumomab, blasts cells have become negative for CD19. 2) Bone marrow biopsy on D826: the bone marrow contained an interstitial infiltrate of blastic cells (arrows) (A), which were positive for PAX5 (B), BCL2 (C) while only a minority were faintly positive for CD19 (D).

Considering the potential efficacy of daratumumab in R/R ALL [7,8,9,10] and the expression, by lymphoblasts, of high CD38 levels, a therapy targeting both BCL-2 (venetoclax 100 mg, Day3-7) and CD38 (daratumumab, 16 mg/kg, on Day2 and Day10) was administered with cyclophosphamide (150 mg/m2 bid Day1-3) and clofarabine (20 mg/m2 Day1-5) to achieve molecular CR. Prolonged agranulocytosis (43 days) was induced with complete hematopoietic reconstitution and molecular CR achieved (sensitivity :< 0.003% ABL and <10−4 or 10−5 for IGH rearrangement depending on the marker). MRD remained undetectable during the 5-month delay between the hematopoietic reconstitution and the second ASCT, with a matched unrelated donor. Twelve months post-ASCT, the patient is in molecular CR under venetoclax maintenance with full donor chimerism.

This case illustrates a successful salvage therapy for a very high-risk R/R KMT2A-AFF1 positive B-ALL, expressing CD38 and BCL-2, but negative for CD19, CD20, and CD22. To overcome chemoresistance, we chose to combine chemotherapy with the BCL-2 inhibitor venetoclax to promote the apoptosis of both lymphoblasts and immature KMT2A-mutated leukemia, which may switch to a myeloid phenotype [11]. In order to achieve a deep and sustained molecular remission before ASCT, venetoclax was then combined with the anti-CD38 monoclonal antibody daratumumab, which can induce cell apoptosis via antibody- and complement-dependent cellular cytotoxicity and promote antibody-dependent cellular phagocytosis [12]. Considering the early relapse after FLAG-Ida salvage chemotherapy, the failure to achieve molecular CR with the cyclophosphamide-including induction therapy, and a salvage regimen containing clofarabine and cytarabine; daratumumab and venetoclax most likely played a major role in obtaining the complete molecular response with an undetectable MRD. This hypothesis is further supported by results of ongoing clinical trials and case reports, which show that venetoclax [13] and/or daratumumab [7,8,9,10], can eradicate MRD in R/R B-ALL or high-risk T-ALL. This case highlights the importance of the sequential assessment of immunotherapeutic target at the surface of lymphoblasts during the course of treatment, and of the potential role of targeting BCL-2 and CD38 antigen in R/R B-ALL, in particular after CD19 antigen loss following CD19-targeted immunotherapies.

Availability of data and materials

Not applicable.

Abbreviations

R/R:

relapsed/refractory

B-ALL:

B-cell acute lymphoblastic leukemia

ASCT:

allogeneic hematopoietic stem cell transplantation

PCR:

Polymerase chain reaction

CR:

complete remission

MRD:

minimal residual disease

IGH:

immunoglobulin heavy chain

DLI:

donor lymphocyte infusion

References

  1. Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120:2032–2041.

    Article  Google Scholar 

  2. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–847.

    CAS  Article  Google Scholar 

  3. Faderl S, Thomas DA, O’Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011;11:54–9.

    CAS  Article  Google Scholar 

  4. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a metaanalysis. JAMA Oncol. 2017;3.

  5. Benito JM, Godfrey L, Kojima K, et al. MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep. 2015;13:2715–2727.

    CAS  Article  Google Scholar 

  6. Khaw SL, Suryani S, Evans K, Richmond J, Robbins A, Kurmasheva RT, Billups CA, Erickson SW, Guo Y, Houghton PJ, Smith MA, Carol H, Roberts AW, Huang DCS, Lock RB. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood. 2016 Sep 8;128(10):1382-95. doi: https://doi.org/10.1182/blood-2016-03-707414. PMID: 27343252

  7. Daratumumab at the frontiers of post-transplant refractory T-acute lymphoblastic leukemia-a worthwhile strategy? Bonda A, Punatar S, Gokarn A, Mohite A, Shanmugam K, Nayak L, Bopanna M, Cheriyalinkal Parambil B, Khattry N. Bone Marrow Transplant. 2018 Nov;53(11):1487-1489. doi: https://doi.org/10.1038/s41409-018-0222-5. Epub 2018 Jun 8. PMID: 29884853

  8. Immunomodulatory and clinical effects of daratumumab in T-cell acute lymphoblastic leukaemia. Cerrano M, Castella B, Lia G, Olivi M, Faraci DG, Butera S, Martella F, Scaldaferri M, Cattel F, Boccadoro M, Massaia M, Ferrero D, Bruno B, Giaccone L. Br J Haematol. 2020 191(1):e28-e32. doi: https://doi.org/10.1111/bjh.16960. Epub 2020 Jul 19. PMID: 32686081

    CAS  Article  Google Scholar 

  9. Daratumumab for eradication of minimal residual disease in high-risk advanced relapse of T-cell/CD19/CD22-negative acute lymphoblastic leukemia. Ofran Y, Ringelstein-Harlev S, Slouzkey I, Zuckerman T, Yehudai-Ofir D, Henig I, Beyar-Katz O, Hayun M, Frisch A. Leukemia. 2020;34(1):293–295. doi: https://doi.org/10.1038/s41375-019-0548-z. Epub 2019 Aug 21. PMID: 31435023

    Article  Google Scholar 

  10. Daratumumab for quick and sustained remission in post-transplant relapsed/refractory acute lymphoblastic leukemia. Zhang Y, Xue S, Liu F, Wang J. Leuk Res. 2020;91:106332. doi: https://doi.org/10.1016/j.leukres.2020.106332. Epub 2020 Feb 24. PMID: 32126433

    CAS  Article  Google Scholar 

  11. Haddox CL, Mangaonkar AA, Chen D, Shi M, He R, Oliveira JL, Litzow MR, Al-Kali A, Hogan WJ, Elliott MA. Blinatumomab-induced lineage switch of B-ALL with t(4:11)(q21;q23) KMT2A/AFF1 into an aggressive AML: pre- and post-switch phenotypic, cytogenetic and molecular analysis. Blood Cancer J. 2017;7(9):e607.

    CAS  Article  Google Scholar 

  12. Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: A first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol. 2016;9(1):51. Doi: https://doi.org/10.1186/s13045-016-0283-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Jain N, Stevenson KE, Winer ES, et al. A multicenter phase I study combining venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic leukemia. Blood. 2019. 134 (suppl 1; abstr 3867).

Download references

Acknowledgements

With thanks to Valentin Basset for the flow cytometry analysis and for providing part of the figures and to Jeanette Carr Klappert for her careful English review.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

SV, SB and OS were in charge of the patient, did the literature review and wrote the manuscript. LdL performed the analyses of the bone marrow. JS and FS performed the genetic and molecular analyses. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Sophie Voruz or Olivier Spertini.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The patient gave his written consent to this publication.

Competing interests

The authors report no conflicts of interest in this work.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Additional file 1:

Supplementary material. Bone marrow aspiration at diagnosis (A+B), first relapse (Day 673; C+D) and second relapse (Day 826; E+F). MGG staining x 100 (A, C, E) and x 400 (B, D, F).

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Voruz, S., Blum, S., de Leval, L. et al. Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript. Biomark Res 9, 92 (2021). https://doi.org/10.1186/s40364-021-00343-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40364-021-00343-3

Keywords

  • Relapsed/refractory B-cell precursor acute lymphoblastic leukemia
  • Adult B-cell lymphoma/leukemia
  • Targeted treatment
  • Chemotherapy regimen
  • Daratumumab
  • CD38
  • venetoclax
  • Bcl-2
  • Refractory disease
  • Immunotherapies