Ambulatory Hematopoietic Stem Cell Transplantation in Young Adults with Acute Myeloid Leukemia Treated with Venetoclax and Low Doses of Cytarabine: Report of Two Cases

Introduction

The treatment of acute myelogenous leukemia (AML) depends on age, functional status, disease status, and cytogenetic risk.^1,2 Young adults receive induction given their proven benefit over supportive and palliative chemotherapy. However, conventional combination therapies have not led to significant progress in the treatment of AML. ³ Allogeneic hematopoietic stem cell transplantation (HSCT) remains a curative approach for high-risk AML.^4,5

Venetoclax is the first drug approved by the FDA which acts directly against the protein of B-cell lymphoma 2 (BCL-2) in cancer. BCL is part of the p53 signaling pathway and regulates apoptosis. ⁶ This protein (BCL-2) has a substantial role in the survival of AML cancer cells because it participates in the apoptotic pathway. ⁷ Venetoclax has been authorized for AML treatment in elderly patients as well as recurrent and/or refractory chronic lymphoid leukemia. ⁸

Clinical trials with venetoclax in combination with cytarabine and other agents are currently underway. ⁹ We present a series of cases of patients with AML managed with low doses of cytarabine and venetoclax, showing a complete response and then underwent to HSCT.

Patient 1

A 20-year-old Afro-descendant woman from the Dominican Republic was diagnosed with AML in August 2016, FAB M4, normal karyotype, immunophenotype CD33+, CD13+, CD34+. She received 3 + 7 (doxorubicin and cytarabine) induction to remission, without achieving a response to treatment. In January 2018, she moved to Mexico with refractory AML, where she received reinduction chemotherapy with mitoxantrone, etoposide, and cytarabine obtaining a partial response. Afterward she was given low-dose subcutaneous daily cytarabine (50 mg/day) and 400 mg oral daily venetoclax for 30 days (Fig. 1) and G-CSF (granulocyte colony-stimulating factor) support during treatment according to neutrophil counts.

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FIG. 1.

Description of the induction and conditioning regimen: Venetoclax and low doses of cytarabine used in both patients in the induction. Conditioning pretransplant patient 1 with melphalan, cyclophosphamide, fludarabine, and cyclophosphamide post-transplant; patient 2 with busulfan, cyclophosphamide, and fludarabine.

Then, complete remission was detected with bone marrow (BM) aspirate with 0% blasts and minimal residual disease (MRD) by 8-color flow cytometry was negative (<0.01). In April 2018, the patient received a peripheral blood stem cell haploidentical transplant from a 43-year-old female donor (mother) with HLA 7/10. The conditioning regimen included melphalan, cyclophosphamide, and fludarabine; +3 and +4 post-transplant cyclophosphamide (Fig. 1); mycophenolate mofetil + cyclosporine was used for graft-versus-host disease (GVHD) prophylaxis starting on +5 day. Antibiotic prophylaxis was provided with fluconazole, levofloxacin, and acyclovir. She received 7.1 × 10⁶ unmanipulated CD34/kg. After the transplant the patient did not show any clear evidence of GVHD; neutrophil engraftment was achieved on day +16 and platelet on day +21.

On day +33 BM MRD by 8-color flow cytometry was negative (<0.01) and chimerism of 97%.

She presented good tolerance to venetoclax and low doses of cytarabine; only showed adverse effects of grade 2, such as gastrointestinal intolerance, decreased appetite, fatigue, and adverse effects of grade 3, such as febrile neutropenia and thrombocytopenia.

During outpatient follow-up, she developed reactivation cytomegalovirus and vertebral aspergillosis, both treated inpatient with ganciclovir, voriconazole, and blood transfusions (four aphereses of platelets and three red blood cell concentrate).

Patient 2

A 37-year-old man with a diagnosis of AML on May 2016, FAB M4, immunophenotype CD33+, CD13+, CD34+, 57% of myeloblasts; no cytogenetic alterations were observed, and he was treated with 3 + 7 (mitoxantrone + cytarabine) achieving complete morphological remission and negative MRD.

In April 2018, a BM relapse was documented with 22% of myeloid blasts. Readmitted to the hematology service with the diagnosis of relapsed AML, for the administration of chemotherapy; low doses of cytarabine (50 mg/day) administered subcutaneously for 30 days and 400 mg oral daily venetoclax for 30 days (Fig. 1) and postchemotherapy prophylaxis with filgrastim. Subsequently, morphologic M1 complete remission, and negative MRD detected by 8-color flow cytometry (<0.01) were achieved. In July 2018, the patient received a peripheral blood allogeneic transplant from a 10/10 HLA compatible female donor (sibling).

The conditioning regimen included busulfan, cyclophosphamide, and fludarabine without anticonvulsant prophylaxis (Fig. 1).

GVHD prophylaxis was done with intramuscular methotrexate 15 mg on day +1, +3, and +5 and oral cyclosporine. Antibiotic prophylaxis was provided with fluconazole, levofloxacin, and acyclovir. He received 3.5 × 10⁶ unmanipulated CD34/kg.

After transplantation, the patient was maintained on oral cyclosporine. Neutrophil engraftment was obtained on day +13 and platelet on day +15. On day +33 BM MRD by 8-color flow cytometry was negative (<0.01) and chimerism of 92%. The day +51 post-transplant presented acute GVHD grade II.

He showed good tolerance to venetoclax and low doses of cytarabine; only showed adverse effects grade 3, such as neutropenia, febrile neutropenia, and thrombocytopenia.

During outpatient follow-up, febrile neutropenia developed and was treated with antibiotics and blood transfusions (two aphereses of platelets and one red blood cell concentrate).

Discussion

We describe patients with AML refractory to treatment and in relapse. They received a scheme with venetoclax and low doses of cytarabine, followed by HSCT, previously conditioned with cyclophosphamide, fludarabine, melphalan, or busulfan.

Both patients received only one cycle of venetoclax and low cytarabine, achieving a negative MRD. This could be a good bridge for transplant.

There are studies in young adults where venetoclax has been used, such as the study by Anderson et al. where they treated patients older than 20 years with chronic lymphocytic leukemia. ¹⁰

The study by Hecker et al. (2018) mentions that venetoclax and low doses of cytarabine may be a feasible bridge strategy for transplantation, reporting complete remissions of 62%. ¹¹ We also use this combination as a bridge strategy for transplantation, achieving complete remission in both cases.

In the study by Wei et al., 82 elderly patients with AML were treated, they received 600 mg/day of venetoclax for 28 days and low doses of cytarabine 20 mg/(m²·d) for 10 days; the average age of response primary was 1.4 months with complete remission of 54% and adverse effects of grade 3 (febrile neutropenia, thrombocytopenia, and neutropenia). ¹²

For both patients, we used lower doses of venetoclax (400 mg) in 30 days and higher doses of cytarabine (50 mg/day) for 30 days.

Reduced-intensity transplants have multiple benefits: they are less toxic, a conventional BM transplant unit is not required, and the cost is lower. In total 60% of patients with AML obtain good results in the medium term. ¹³

Conclusion

Venetoclax combined with low dose of cytarabine may be a viable therapeutic option for young adult patients with relapsed or refractory AML, and also could be a good bridge strategy for HSCT.

This combination is used in elderly patients with good results and we believe that it can be extrapolated to young adults with AML in relapse or refractory to treatment.

Reduced-intensity transplant therapy is a good alternative to consolidate patients with relapsed or refractory acute myeloid leukemia who achieve remission with venetoclax and low doses of cytarabine.