Chemotherapy-Free Achievement of Minimal Residual Disease in a Jehovah’s Witness Patient With Ph-Negative B-ALL

Introduction

Acute lymphoblastic leukemia (ALL) is the second most common leukemia among adults, with approximately 6500 new cases diagnosed in the United States annually [1]. B-cell lymphoblastic leukemia (B-ALL) represents around two-thirds of all ALL cases and is generally classified into subtypes according to Philadelphia chromosome (Ph) status [2]. Ph-negative B-ALL is now considered potentially curable with intensive chemotherapy regimens and allogeneic transplantation.

Despite recent therapeutic advances, treatment of ALL in the Jehovah’s Witness population presents considerable ethical and clinical challenges. Most Jehovah’s Witness patients refuse blood products, which are essential for managing the severe anemia and thrombocytopenia caused by the disease and its treatment. In a typically healthy young patient, Ph-negative B-ALL is usually treated with intensive chemotherapy that includes cyclophosphamide, vincristine, anthracyclines, and dexamethasone [3]. However, these regimens may not be feasible for Jehovah’s Witness patients, due to their refusal of blood products during periods of profound myelosuppression. Avoiding agents with substantial bone marrow toxicity would broaden treatment options for this population.

Intensive chemotherapy is also unsuitable for many older patients. Individuals 60 years and older with Ph-negative B-ALL receiving intensive chemotherapy have poor outcomes, with a 1-year overall survival (OS) of only 6% to 20% [4]. Recently, new targeted agents such as blinatumomab, a bispecific T-cell engager antibody, and inotuzumab ozogamicin, an antibody–drug conjugate, have emerged as favorable options for older patients or younger patients with comorbidities such as reduced cardiac function. These agents were initially used in relapsed or refractory disease; in 2023, the ALLIANCE trial showed that inotuzumab and blinatumomab are effective as first-line treatments [5].

We describe a case of a 44-year-old Jehovah’s Witness man with Ph-negative B-ALL and reduced cardiac function who received a chemotherapy-free regimen of inotuzumab induction followed by blinatumomab consolidation in the frontline setting. To our knowledge, this case represents the first reported instance in which a Jehovah’s Witness patient with Ph-negative B-ALL received a chemotherapy-free regimen as initial therapy.

Case Report

A 44-year-old Jehovah’s Witness Caucasian man with a history of hypertension, hyperlipidemia, atrial fibrillation, chronic obstructive pulmonary disease, and diabetes mellitus presented to the hospital with nausea, vomiting, and diarrhea, which had been present for 3 days. His initial laboratory results revealed pancytopenia with a white blood cell count of 1500 cells/μL (reference: 4500–11,000 cells/μL), hemoglobin level of 10.8 g/dL (reference: 12.6–16.7 g/dL), and platelet count of 71×103/μL (reference: 139–361×103/μL). He had severe neutropenia with an absolute neutrophil count of 0.1×103/μL (reference: 1.5–7.5×103/μL).

A computed tomography scan of the abdomen and pelvis showed moderate hepatosplenomegaly. A peripheral blood smear demonstrated microcytic anemia, pronounced leukopenia, and thrombocytopenia, without evidence of peripheral blasts. An extensive laboratory evaluation was nondiagnostic and showed no findings consistent with vitamin deficiency, hemolysis, coagulopathy, or autoimmune disease. Bone marrow biopsy revealed hypercellular marrow (80%) with B-ALL involvement, comprising approximately 25% of cells (Figure 1). Flow cytometry identified a population of 25% abnormal B lymphoblasts. Immunohistochemistry results showed cluster of differentiation (CD)34, paired box gene 5 (PAX5), CD117, E-cadherin, and CD138 positivity; they showed terminal deoxynucleotidyl transferase negativity. Next-generation sequencing results for BCR-ABL were negative, confirming a diagnosis of Ph-negative B-ALL. Cytogenetic analysis showed a normal male karyotype. ALL-specific fluorescence in situ hybridization results were negative for erythropoietin (EPOR) and cytokine receptor-like factor 2 (CRLF2) rearrangements, and ALL NeoType® detected no mutations.

Before initiation of ALL-directed therapy, a baseline echocardiogram demonstrated a newly reduced ejection fraction of 30% to 35%. Further evaluation with left heart catheterization indicated moderate coronary artery disease, and cardiac magnetic resonance imaging findings were negative for significant infiltrative or ischemic etiologies. As a Jehovah’s Witness, the patient declined transfusions due to religious beliefs. Because his reduced cardiac function precluded anthracycline-based therapy and his refusal of blood products limited cytotoxic chemotherapy options, a chemotherapy-free regimen of inotuzumab and blinatumomab was selected to reduce cytopenias and cardiotoxicity. He continued taking chronic medications, including losartan, metoprolol, spironolactone, empagliflozin, and apixaban. Diabetes was managed with sliding-scale insulin. He also received prophylactic intravenous iron sucrose 200 mg weekly for 3 doses, daily folic acid and vitamin B12 supplementation, epoetin alfa 40 000 units weekly if the hemoglobin level declined below 12 g/dL, and romiplostim 4 μg/kg weekly if platelet count was below 100×103/μL.

While hospitalized, the patient received course 1A of induction therapy with inotuzumab 0.5 mg/m2 on days 1, 8, and 15, as well as a single dose of intrathecal methotrexate for central nervous system prophylaxis. Cerebrospinal fluid analysis results indicated no leukemic involvement. He tolerated induction therapy well, with minimal adverse effects limited to grade 1 fatigue and grade 1 nausea. Pancytopenia substantially improved after initiation of inotuzumab, and growth factor support was rarely required. He received epoetin alfa twice, after which further doses were withheld because his hemoglobin level remained above 12 g/dL. He required romiplostim only once; his platelet counts stayed above 100×103/μL. Neutropenia also substantially improved after the first dose of inotuzumab, with absolute neutrophil counts ranging from 0.9 to 1.4×103/μL throughout induction. Despite the absence of severe neutropenia, the patient continued to receive acyclovir, levofloxacin, and posaconazole for neutropenic fever prophylaxis.

On day 20, bone marrow biopsy was performed to assess treatment response. It showed normocellular marrow (50%) with trilineage hematopoiesis and no morphological evidence of residual B-ALL (Figure 2). Flow cytometry findings were negative for residual leukemia. Cytogenetic analysis showed a normal male karyotype, ALL-specific fluorescence in situ hybridization results were normal, and ALL NeoType® findings were negative. ClonoSEQ detected minimal residual disease (MRD) with 19 residual clonal cells per million nucleated cells. The patient was discharged from the hospital on day 20. At discharge, he remained neutropenic with an absolute neutrophil count of 1.0×103/μL; however, hemoglobin and platelet counts were within normal limits.

Complete morphologic remission was achieved after course 1A of inotuzumab; course 1B with inotuzumab 0.5 mg/m2 on days 1, 8, and 15 was initiated as outpatient therapy. He received intrathecal methotrexate once for central nervous system prophylaxis, and cerebrospinal fluid analysis results indicated no leukemic involvement. He completed course 1B of inotuzumab without serious adverse effects. Repeat bone marrow biopsy demonstrated no morphological evidence of residual leukemia, and ClonoSEQ confirmed MRD negativity with zero residual clonal cells per million nucleated cells (Figure 3). He tolerated course I of blinatumomab aside from grade 1 cytokine release syndrome, which resolved after 1 dose of dexamethasone. This case is notable because it involved the rare use of a chemotherapy-free regimen in a Jehovah’s Witness patient with Ph-negative B-ALL.

Discussion

Treating Ph-negative B-ALL in Jehovah’s Witnesses remains a challenge for hematologists. The inability of such patients to receive blood products often limits use of intensive chemotherapy, which typically offers the highest response rates and survival benefits. New targeted therapies, such as blinatumomab and inotuzumab, have emerged as effective alternatives for older patients who cannot tolerate aggressive chemotherapy. However, data specific to Jehovah’s Witness patients are limited, and no established standard of care exists for this population.

Generally, the 5-year OS for Ph-negative B-ALL treated with conventional chemotherapy – such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyper-CVAD) – considerably varies according to age. In younger adults, the 5-year OS is approximately 70%, whereas in older adults it may decrease to 20% [6]. Historically, patients aged 60 years and older receiving hyper-CVAD experienced high induction mortality despite dose adjustments [7]. Consequently, the treatment paradigm shifted toward low-intensity chemotherapy (mini-hyper-CVAD) combined with fractionated inotuzumab, which produced improved outcomes. This regimen resulted in 0% early mortality versus 5% with full-dose hyper-CVAD. Additionally, the 3-year event-free survival and OS rates with hyper-CVAD were both 34%, versus 64% and 63%, respectively, for mini-hyper-CVAD plus inotuzumab [8].

Similar to older adults, Jehovah’s Witness patients cannot safely undergo standard chemotherapy regimens because they cannot receive transfusion support. However, evidence guiding treatment decisions for this group is sparse. A 2004 study included 11 Jehovah’s Witness patients with acute leukemia, 5 of whom had ALL. These patients received standard doses of vincristine and prednisone; daunorubicin was administered at a reduced dose. Four of the 5 patients achieved complete responses, although 2 relapsed at 10 and 13 months [9]. A 2010 case report described a patient with ALL receiving standard-dose induction chemotherapy who developed severe anemia and was treated with a polymerized bovine hemoglobin–derived artificial oxygen carrier until bone marrow recovery occurred [10].

In 2022, a case series included 6 Jehovah’s Witness patients with ALL; 4 had Ph-negative B-ALL, and 2 had T-cell ALL. The case series demonstrated that remission can be achieved with vincristine, prednisone, and pegaspargase alone, initially avoiding anthracyclines, which may be added later at reduced doses if blood counts permit. Five of the 6 patients showed molecular remission after induction, and 2 achieved long-term durable remission. One patient with Ph-negative B-ALL who experienced early relapse was treated with blinatumomab and has remained in remission for 60 months post-diagnosis [11]. The ALLIANCE A041703 trial [5] enrolled patients aged 60 to 84 years with newly diagnosed Ph-negative, CD22-positive B-ALL. Participants received induction therapy with inotuzumab ozogamicin, followed by consolidation with blinatumomab. The primary endpoint of this phase II trial was 1-year event-free survival, achieved by 75% of patients. Approximately 85% reached complete remission without chemotherapy, and 70% showed MRD negativity at the end of consolidation. This trial demonstrated an effective treatment alternative for older adults with Ph-negative, CD22-positive B-ALL. Although our patient was younger than 60 years, we pursued induction with inotuzumab followed by consolidation with blinatumomab, guided by the ALLIANCE A041703 trial, because conventional chemotherapy carries a high risk of myelosuppression and he was unable to receive anthracyclines due to reduced cardiac function. Prophylactic intravenous iron, oral vitamin B12 and folate supplementation, erythropoiesis-stimulating agents, and thrombopoietin receptor agonists were used to reduce the risks of anemia and thrombocytopenia.

To date, the patient has completed 2 cycles of inotuzumab and 1 full cycle of blinatumomab; he has tolerated therapy well aside from brief episodes of grade 1 fatigue, nausea, and cytokine release syndrome. He did not experience clinically significant cytopenias during treatment, and he required erythropoiesis-stimulating agents and romiplostim only once. Although he showed MRD positivity according to ClonoSEQ after his first cycle of induction, he achieved MRD negativity after his second cycle of inotuzumab. He is currently scheduled to complete 4 total cycles of blinatumomab and continues to maintain a strong performance status.

Conclusions

To our knowledge, this case represents the first reported instance in which a Jehovah’s Witness patient with Ph-negative B-ALL received a chemotherapy-free regimen as initial therapy. The patient tolerated treatment well, without serious adverse effects or cytopenias, and achieved MRD negativity according to ClonoSEQ after 2 cycles of inotuzumab. Future trials should consider including Jehovah’s Witness patients to optimize ALL treatment strategies in this unique population. Induction with inotuzumab followed by consolidation with blinatumomab, as outlined in the ALLIANCE trial, appears both feasible and promising for patients unable to undergo intensive chemotherapy, offering an excellent therapeutic option for Jehovah’s Witness patients with Ph-negative B-ALL.