Chemotherapy without Blood Products for Treatment of Acute Myelogenous Leukemia in an Anemic Jehovah’s Witness Patient

Introduction

Acute myelogenous leukemia (AML) is an aggressive, rare malignancy that originates in the stem cells of all myeloid precursors, except for B and T cells [1]. Compared to other malignancies in the United States, AML is rare, accounting for roughly 1.2% of all new cancer diagnoses in the United States per year [1,2]. Adults typically present with signs of anemia and a hemogram that reveals pancytopenia with blast cells. A bone marrow biopsy is used to diagnose the condition. The malignancy is classified by subtype and risk status using morphological analysis, cytogenetic analysis, fluorescent in situ hybridization (FISH), flow cytometric immunophenotyping, and molecular testing [3–5].

Jehovah’s Witness (JW) adherents refuse blood transfusions and blood-related products, which creates unique challenges for medical practitioners treating patients with AML [4]. This refusal is particularly significant due to the risk of severe cytopenia arising not only from traditional intensive chemotherapy regimens but also from the disease itself. The conventional treatment regimen causes severe marrow aplasia, rendering patients temporarily transfusion-dependent [6]. A JW who refuses to accept any blood transfusion is typically treated with a less aggressive regimen of a hypomethylating agent plus B-cell lymphoma 2 (Bcl-2) inhibitor, which causes less severe cytopenia compared with the traditional intensive induction chemotherapy [7,8]. The present report is the first reported case of an individual with high-risk AML and a starting hemoglobin below 8 g/dL who declined blood transfusion. Because of the unique patient-dictated treatment requirements of JW patients and the high risk of marrow suppression and drug reactions, customized chemotherapeutic regimens that are less marrow-toxic have been published. Although drugs with lower toxicity may be available in the future, treatment regimens based on lower doses of standard chemotherapeutic drugs are currently used for patients who refuse blood products. We present a JW woman in her late twenties with severe baseline anemia diagnosed with high-risk AML treated with a hypomethylating agent plus Bcl-2 inhibitor without any blood product transfusions in a community hospital setting.

Case Report

A JW woman in her late twenties with a past medical history of iron deficiency anemia presented to our emergency department with complaints of bruising and heavy menstrual periods over the past several months. The patient reported that for the past 4–8 weeks, she had been experiencing palpitations, headaches, and fatigue. Three weeks prior, she was seen at her primary care physician’s office for these complaints, and she was found to have a hemoglobin of 7.3 g/dL (the reference range for women is between 12.3 g/dL and 15.3 g/dL). She had a repeat hemoglobin measurement 2 weeks later, which showed a hemoglobin of 7.2 g/dL. On admission, her vitals were as follows: blood pressure, 113/71 mmHg; pulse, 77 beats per minute; temperature, 36.9°C (98.4°F); respiratory rate, 23 breaths per minute; and oxygen saturation (SpO2), 100% on room air. Her initial lab values for her first admission are shown in Table 1.

Her physical examination revealed a pale woman with no bruising or skin lesions. Mucous membranes were intact and there was no hepatomegaly. Her family history was noncontributory. Iron stores showed severe iron deficiency, with normal vitamin B12 and folic acid. Additional workup on her first admission for anemia and leukopenia included a negative antinuclear antibody (ANA) test, a negative hepatitis panel, a negative HIV test, and a normal thyroid-stimulating hormone level. Her peripheral blood smear showed increased blast presence. Hematology recommended a bone marrow biopsy for further evaluation. The time from admission to diagnosis was fast. A bone marrow aspiration and core biopsy were performed on day 3 of her first admission for confirmation of morphological diagnosis and for further molecular testing. The bone marrow results were positive for 70% blasts (95% cellularity), consistent with AML. Immunohistochemistry was positive for CD2, CD7 (partial), CD13, CD15, CD33 (partial), CD34, CD38, CD45 (dim), CD117, and human leukocyte antigen – DR isotype (HLA-DR; partial). Testing from NeoGenomics Laboratories revealed unique genetic abnormalities, including a deletion of chromosome 8q and FISH significant for atypical loss of neurofibromin 1 (NF1), located at chromosome 17q11.2. Given her low white blood cell count (less than 10 000 cells per microliter), she was diagnosed with low-risk acute promyelocytic leukemia, a subtype of AML.

Her counseling was detailed. We discussed the AML diagnosis, treatment options, and prognosis. She understood that her case, a JW with AML refusing to take blood who was starting induction therapy profoundly anemic, was rare. The patient and her family were advised to be transferred to a tertiary center with high experience in bloodless medicine. The patient declined this option for social reasons by signing a consent. An expert consultation with a bloodless medicine expert treating AML at a tertiary center was obtained. Since the patient refused to grant consent to accept any blood product and she was already severely cytopenic, it was decided that the most appropriate treatment plan would be a less aggressive regimen with a hypomethylating agent (IV azacytidine 300 mg daily for 7 days) plus oral venetoclax (a BCL-2 inhibitor) 100 mg daily for 7 days. The dose of venetoclax was reduced due to the concomitant use of posaconazole, as a more aggressive regimen would have a very high risk of morbidity and mortality without a transfusion. Treatment started with an effort to address her anemia and provide prophylaxis from infectious agents. Her iron stores were replaced on her first admission with IV iron infusions in addition to daily oral vitamin B12 and folic acid supplements. She was also given a weekly erythropoietin injection after discussion of the benefits and risks of erythropoietin in myeloid malignancies. A review of her medications and bone marrow results is presented in Table 2. Fourteen days into her treatment, her hemoglobin level was at 3.9 g/dL, and her platelet count reached a nadir of 27 000 platelets/μL (Table 3). The patient was scheduled to start azacytidine. However, the patient started to menstruate and was discharged with oral trans-4-(aminomethyl) cyclohexane carboxylic acid (tranexamic acid) and weekly epoetin alfa with instructions to return in a week for induction of chemotherapy. She was also started on epoetin alfa 20 000 units daily subcutaneously. At the time of discharge for her menstruation, her hemoglobin was 5.9 g/dL and her platelet count was 107 000 platelets/μL.

The patient was readmitted 7 days later for inpatient chemotherapy, receiving azacytidine at a dose of 75 mg/m2 for 7 days and venetoclax at a reduced dose of 100 mg (due to interaction with posaconazole and in the context of no possibility of blood transfusion) for 7 days only. A bone marrow biopsy was performed again on day 28. The patient was discharged on levofloxacin, voriconazole, and weekly darbepoetin on day 32.

During her 1-week follow-up appointment, the results of the second biopsy showed residual leukemia with 10–15% blasts. The patient’s hemoglobin had recovered to 9.5 g/dL. A list of her serial hemoglobin, white blood cell count, and platelet results is presented in Table 3. Due to severe anemia from venetoclax plus azacytidine and her continued refusal of all blood products, we proceeded with monotherapy with azacytidine 75 mg/m2 for 5 days.

She was counseled extensively about the risk of disease persistence and relapse and was recommended options for treatment. She was not a candidate for hematopoietic stem cell transplantation. She was again advised of the aggressive nature of her AML and the need for additional chemotherapy pending laboratory results on her follow-up checks with the hematology and oncology team. She understood the association between her condition and the high mortality caused by severe anemia, the lower rate of remission, and the extremely low chance for sustained remission. A minimum of 6 cycles of treatment was discussed. She received 2 outpatient cycles of 7 days of azacytidine with a 28-day rest but refused to continue due to worsening fatigue. She was offered low-dose metabolically optimized dexamethasone and venetoclax, which she refused. She declined hospice care at home or facility despite multiple discussions. She also declined home health services. She received supportive care, provided by her family, including as-needed oxygen supplementation. The reasons for her choices were personal, and she died at home with severe anemia of 2.1 g/dL.

Discussion

This case is unique for 2 reasons. First, this patient was a severely anemic JW who declined blood product transfusion and presented with adverse risk AML [1,4]. Second, her diagnosis and treatment were in a community healthcare setting.

Her tumor exhibited unique genetic abnormalities, including abnormalities in chromosome 8q and a FISH result significant for atypical loss of NF1 located at chromosome 17q11.2. Specific alterations in FLT3, IDH1, and IDH2 were absent [5]. The finding of NF1 mutations may be associated with worse outcomes in younger AML patients [5], but the absence of mutations in FLT3, IDH1, and IDH2 genes suggested a more favorable prognosis [9]. Unfortunately, as this case demonstrates, even with favorable mutations, starting with anemia and not treating bone marrow disease of this type with necessary blood products is an insurmountable risk factor. Fleisman indicated that with a comparable chemotherapy regimen, 70% of patients will need red blood cell transfusions, and 58.6% will require platelet transfusions at some point during or after chemotherapy induction [10]. Our patient was definitely a candidate for transfusion, considering she had a low hemoglobin of 3.7 g/dL on day 17 of her first cycle. It was clear from the beginning that treatment in this case would be complicated.

Reports of AML in JW are uncommon in the literature, likely secondary to the high mortality rate associated with treatment-related cytopenia. To date, no other case reports of JW refusing blood products for the treatment of AML have had a starting hemoglobin level below 7.3 g/dL. A 2016 report [8] indicated that administering low-dose chemotherapy for AML in JW patients resulted in lower remission rates, higher relapse rates, and increased mortality due to severe anemia. Their patient received treatment with cytosine arabinoside (Ara-C), valproic acid, and vinblastine, and survived for 8 months without the need for transfusions. However, cytogenetic and molecular studies were not performed, so it is difficult to know which risk category the patient belonged to. Her starting hemoglobin was 8.6 g/dL [8]. This regimen was an option for our patient, but the risk status of her malignancy was not listed, which was a reason to offer our patient the alternative option. In a 2020 case study reported by Bock and Pollyea [11], 2 JW patients with high-risk AML underwent treatment with reduced doses of azacytidine and venetoclax, achieving durable remission without the need for transfusion. The hemoglobin values for these 2 patients at the start of induction were 11 g/dL and 12.7 g/dL, which exceeded our patient’s starting hemoglobin of 6.1 g/dL on day 1 of induction. Our patient never achieved remission with a similar drug regimen, but her severe anemia limited the dosing. Page et al [12] also presented a 76-year-old JW successfully treated with azacytidine and venetoclax for AML. The patient’s starting hemoglobin was 10.7 g/dL, and he successfully completed 9 cycles of azacytidine and venetoclax [12]. In our case, induction was started with the same regimen. However, ours is unique due to the low levels of hemoglobin both before and during chemotherapy.

The venetoclax and azacytidine (VIALE-A) trial [6] was a landmark trial that established a new standard of care for patients who are unfit or ineligible for traditional intensive chemotherapy [13]. Data have confirmed that patients declining blood product therapy, regardless of their risk status, will have lower remission rates and a higher mortality attributed to anemia [14]. This is consistent with the findings in our case. Pratz et al [15] demonstrated that venetoclax, in combination with azacytidine, had better outcomes than azacytidine alone. The combination exhibited a higher incidence of febrile neutropenia compared with the group receiving azacytidine plus placebo. No note was made of the consent to take blood products in their study [15]. These findings were among the reasons for our recommendation of the drug regimen used in the present case.

Although the results from the VIALE-A trial recommended azacytidine for 7 days and venetoclax for 28 days, a study by Karrar and colleagues contradicted this regimen [16,17]. They reported treatment of 270 AML patients with varying durations of venetoclax and showed that 14 days of venetoclax was as effective as 21 days or 28 days, with a lower possibility of toxicity and a lower financial burden. A 2022 study introduced the 7+7 scheme, in which azacytidine and venetoclax were administered concurrently on specific days. The study found that this regimen may be as effective as administering azacytidine for 7 days and venetoclax for 28 days [17]. Using the literature for guidance, our patient’s regimen was customized to match the 2022 7+7 regimen. Unfortunately, her hemoglobin fell to critical levels, and her blast percentage remained at 10–15%. The combination of her profound, life-threatening anemia throughout the course of her disease, refusal to take blood products, and her high-risk AML genetic profile resulted in rapid death. Possibly, hematological support that does not require blood products will be available in the future, and a full course of antineoplastic drugs will be available to JW patients with AML and anemia.

One final element in this case is that the patient chose not to travel to a distant or unfamiliar university system. She was diagnosed and treated from start to finish at a community hospital without the infrastructure and support of a university hospital system [18].

The patient was informed of her available care location options. Convenience, trust, and community engagement were key factors in her decision. Treating a patient with a medical condition as if the individual were a hospice patient makes the local care of critically ill conditions noncontroversial. However, a patient who may benefit from tertiary care should be continuously counseled about this option.

Conclusions

In summary, this patient presented with severe anemia and AML, but refused to accept blood transfusions and refused to travel to a tertiary-level hematology/oncology care unit. This is the first reported case of its kind, which made counseling about treatment necessarily complicated. She was offered a regimen that gave her the best chance of treating her malignancy with the least toxic effect on her bone marrow. To glean insight into our case, the entire pertinent literature was reviewed, and a comparison was made between our patient’s treatment and the outcomes reported in the literature. With slight modifications of details, the studies and case reports support our methods of workup and treatment, considering the patient’s refusal of blood products.

Traditionally, the treatment of a chronic, progressive multiorgan health calamity is referred to a university-based or regional care center. However, if the patient and provider agree that the health service is available locally, they can choose the venue with expectations of equivalent outcomes. AML is an aggressive blood cancer that requires active treatment and rigorous follow-up. Both the treatment and the disease cause severe bone marrow suppression, resulting in a high proportion of patients requiring blood product transfusion. JW adherents decline blood; therefore, customized chemotherapeutic regimens that are less marrow-toxic have been published. This case is unique due to the patient’s critically low hemoglobin level at the start of chemotherapy induction and her decision to remain in her local venue. She was encouraged throughout her treatment to engage a tertiary-level Hematology/Oncology program, but was firm in her refusal. The inability to include blood products in the treatment plan severely reduced any expectations with regard to a remission of the malignancy. We conclude that the 7+7 regimen might be effective in an otherwise fit JW woman who has an adverse risk of AML, but serious anemia at the beginning of treatment is an additional risk. The clinical insights gained from managing this complex case emphasize the importance of the need to be ready to adjust therapy during treatment. The clinical relevance of this case focuses on cooperation between care providers at different levels of care. Similar cases treated in the future could include newer drug therapies with lower risks or even hematological support that does not require blood products.