Letter to the Editor: Single agent blinatumumab as frontline therapy for an 85-year old patient with B-cell precursor acute lymphoblastic leukemia

Dear Editor,

The outcomes of older patients with acute lymphoblastic leukemia (ALL) remain dismal and the therapeutic options are limited. We present the case of an 85-year old female with poor renal function who was diagnosed with Philadelphia chromosome-negative B-cell ALL (PH-ve B-ALL) and successfully treated with the bispecific T-cell engager (BiTE) blinatumomab in the upfront setting.

An 85-year old female presented in May 2015 with shortness of breath, fatigue and abdominal pain to a local clinic. She was found to have WBC of 26×10³/μL (normal: 4 ×10³-10×10³/μL), Hemoglobin of 12g/dL (normal: 12–16 g/dL), and platelet count of 16 ×10³/μL (normal 150×10³-350×10³/μL). Bone marrow evaluation was consistent with B-ALL. She was treated with steroids leading to partial improvement in her blood counts and symptoms. Two weeks later she moved to New Haven, CT to be closer to her family and presented to our clinic with fatigue. Her medical history was significant for multiple cancers including estrogen receptor positive, progesterone receptor positive, and HER2-negative T1bN1 invasive ductal carcinoma of the left breast which was treated by lumpectomy in October 2014 followed by radiotherapy. Subsequently she was treated with tamoxifen. She also had a history of Non-Hodgkin B-cell lymphoma treated with CHOP (cyclophosphamide/doxorubicin/vincristine /prednisone) in 1988 and low grade superficial bladder urothelial carcinoma treated with transurethral resection in 2012. Her other comorbidities included stage 3 chronic renal dysfunction, hypertension, hypothyroidism, and gastroesophageal reflux disease. On physical examination she was found to have several ecchymoses on her arms and breasts and a scar on the left breast from lumpectomy, otherwise unremarkable including no hepatosplenomegaly or lymphadenopathy.

Her evaluation at our clinic showed WBC of 4.7×10³/μL (56% neutrophil, 38% lymphocyte, 1% monocyte, 4% eosinophil, 1% basophil), Hemoglobin of 12.9g/dL, and platelet count of 158 ×10³/μL, creatinine 1.2 mg/dL (normal: 0.5–1.2 mg/dL) with a glomerular filtration rate of 43 (>60ml/min/1.73m²), AST 26 (0–34U/L), ALT 11 (0–34U/L), Alkaline phosphatase 71 (30–130U/L), bilirubin 0.40 (<1.20 mg/Dl), uric acid 6.2 (normal: 2.5–6.0mg/dL), phosphorus 3.0 (normal: 2.5–4.5mg/dL).

A bone marrow examination in June 2015 revealed hypercellular marrow with sheets of lymphoblasts (Figure 1). Bone marrow aspirate flow cytometry demonstrated that 90% of bone marrow cells were CD34+ CD45dim+ HLADR+ TdT+ CD19+ CD10subset+ CD20- cytoCD79a dim+ surface immunoglobulin- B lymphoblasts without expression of myeloid or T markers. Fluorescence in situ hybridization (FISH) was negative for t(9;22) but karyotyping showed an abnormal clone with a deletion in the short arm of a chromosome 9 (del9 (p21)) in three out of 20 cells. Additional FISH test was performed using dual color probes for the CDKN2A gene at 9p21 and the D9Z3 locus at 9p12. Of the 200 interphase cells examined 13.5% showed an abnormal pattern of one signal for the CDKN2A probe.

Figure 1.

A) Initial bone marrow showing acute lymphoblastic leukemia on H&E at 10x objective and B) at 40x objective with C) aspirate showing monomorphic blasts with vaculoated basophilic cytoplasm at 60x oil objective. Immunostains include D) TdT, E) CD34 and F) PAX5. After therapy, the marrow core biopsy G) is chemoablated with aspirate H) at 10x showing few scattered maturing cells and is I) negative for TdT.

We discussed with the patient the poor prognosis of ALL in the very elderly, and reviewed the therapeutic challenges including her very advanced age, poor performance status (PS), poor kidney function, and multiple prior cancers and chemotherapy/radiation exposure leading to expectation of poor response and very high rate of treatment-related morbidity and mortality with intensive chemotherapy. Treatment options discussed included supportive care alone or together with low intensity type therapies such as the POMP regimen (prednisone, vincristine, methotrexate, 6-mercaptopurine [6-MP]). We also discussed the use of the BiTE blinatumumab for upfront management. Blinatumumab has been recently approved by the Food and Drug Administration (FDA) for management of refractory/relapsed B-cell ALL in the US[1–3]. This decision was based on high response rates reported in the relapsed/refractory setting and lack of traditional chemotherapy-type toxicities. However, the risks of cytokine release syndrome and neurologic toxicity in an elderly patient with compromised renal function for a drug with lack of documented experience in the upfront setting were concerning and thoroughly discussed [4]. The decision was made to proceed with blinatumumab therapy.

Two cycles of blinatumumab were given for induction. Blinatumumab was administered per label specified continuous infusion in 28-day cycles. The infusion was started at 9mcg/day in the hospital for the first 9 days of the first cycle. With the first cycle, the patient developed hypotension, fever, mental status changes during the early course of treatment as reported before[3]. These symptoms resolved by holding the drug and administration of supportive care, and the infusion was resumed 24 hours later. After 9 days of infusion the dose was escalated to 28mcg/day without problems and the patient was discharged home 2 days later where she completed the 28-day infusion. Her blood counts normalized with the first cycle of blinatumumab (Figure 2). She proceeded to receive the second cycle of blinatumumab after a 2-week break. The second cycle was started in the hospital and was complicated by volume overload and mild hypoxia that resolved with diuresis. Bone marrow evaluation in October 2015 confirmed complete remission (CR, Figure 1) with no evidence of minimal residual disease by flow cytometry. She received total 7 intrathecal (IT) chemotherapy with methotrexate alternating with cytarabine. Her cytology/flow cytometry for spinal fluid had been negative and she does not want any further IT chemotherapy due to personal reason (i.e. severe degenerative joint disease). Subsequently, she started POMP maintenance therapy and remains asymptomatic with excellent PS. She has been in CR for 7 months as of last follow up in May 2016.

Figure 2.

WBC, Hemoglobin, and platelet count upon presentation and during treatment.

Treatment of older patients with PH-ve B-ALL remains very challenging due to poor tolerance of chemotherapy and lack of high quality data. Compared to younger B-ALL patients, older patients have unfavorable biological prognostic factors such as poor cytogenetic abnormalities (Philadelphia chromosome positivity, t(4;11), complex cytogenetic abnormalities) and high prevalence of comorbidities leading to high rates of complications and early mortality. Blinatumumab is a bispecific engager between T cells with one arm binding anti-CD3ε and B cells or lymphoid leukemic cells and the other arm binding anti-CD19 [1,2]. Two recent phase 2 studies in adult patients with relapsed or refractory precursor B-ALL demonstrated that two cycles of single agent blinatumumab achieved 43 and 69% of CR or CR with partial hematological recovery and 6.1 and 9.8 months of median overall survival[5,4]. In December 2014, FDA granted accelerated approval for blinatumomab for the treatment of PH-ve relapsed or refractory precursor B-ALL based on these studies. The use of blinatumumab in relapsed/refractory B-ALL has changed the paradigm of the treatments for this deadly disease in addition to recently approved liposomal vincristine[6] (approved by FDA in 2012) and chimeric antigen receptor T-cell therapy[7]. Our patient is an example of how outcomes of elderly patients with B-cell ALL with co-morbidities can be improved with biologic therapies and that such therapies should be considered when possible. Clinical trials, such as the ongoing SWOG NCT02143414 trial, are required to confirm the benefit of this approach in elderly patients with B-cell ALL who are not candidates for conventional chemotherapy regimens.