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An 83-year-old woman with abnormal blood count, worsening pancytopenia
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A classical conundrum in medicine is the treatment of serious illness in the elderly. Various issues need to be weighed in concert, such as the patient’s overall health, acceptability of certain diagnostic or therapeutic interventions, and end-of-life wishes, among others. A case was recently seen with this backdrop, for the evaluation of a serious hematologic condition.
The patient is an 83-year-old woman with a history of abnormal blood counts for approximately the past 2 years, who was referred for worsening pancytopenia. Her past medical history is notable for rheumatoid arthritis being treated with methotrexate, as well as hypothyroidism, osteoporosis, and hypertension. In 2009, while on methotrexate, she experienced epistaxis, and was found to be pancytopenic. With discontinuation of methotrexate at that time, the pancytopenia largely corrected, except for a mild, chronic normocytic anemia. About 10 months later, she again had a flare of rheumatoid arthritis, and methotrexate was re-instituted. The arthritis symptoms dissipated, but she again developed pancytopenia. Although methotrexate was effective for the arthritis, her rheumatologist requested an investigation about the etiology of the blood dyscrasia, to better select her next treatment option.
History revealed that the patient, interestingly, had an unknown hematologic abnormality in the 1950s, for which she underwent a bone marrow aspiration from the sternum. As far as she understood, the results were “normal.” She did not suffer any subsequent hematologic issues until the cytopenias in 2009. She had not required a transfusion during her clinical course. She was not experiencing any fevers, chills, night sweats, or weight loss.
Initial laboratory data at the time of the consultation showed white blood cell (WBC) count 1,900 /mL; hemoglobin 9.7 gm/dL; MCV 112.7; and platelet count 89,000 /mL. The differential on the WBC count was notable for 63% lymphocytes and 30% neutrophils. Review of the CBC over the past 2 years showed that she had pancytopenia to a similar degree with methotrexate usage in the past. (WBC count range 1,300 to 1,900 /mL; hemoglobin 9 gm to 10 gm/dL; and platelets 70,000 – 100,000 /mL).
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Other laboratory studies showed a normal vitamin B12 level and folic acid level. T-cell receptor gene rearrangement studies from the peripheral blood were negative. Iron studies, renal function, and liver function testing were unremarkable. Physical exam was significant for a palpable spleen tip, but no hepatomegaly or lymphadenopathy.
At this point, the differential diagnosis included the possibilities of methotrexate effect, Felty’s syndrome, autoimmune cytopenias, and primary bone marrow disorders, such as myelodysplasia, given the macrocytosis and pancytopenia, as well as large granular lymphocyte leukemia. It was explained that a bone marrow biopsy may become necessary in such cases, to definitely establish the etiology, particularly since the patient had absolute neutropenia. The patient’s wishes were to try to avoid the biopsy if possible.
Accordingly, and after discussion with her rheumatologist, methotrexate was held, as she had a well-documented temporal correlation between folic acid and pancytopenia. Folic acid supplementation was begun in addition. Within a few weeks, the blood counts improved nicely. However, shortly thereafter, they began to trend downwards again, in spite of continued folic acid supplementation and methotrexate cessation (See Table).
Around the same time, as the blood counts decreased, the patient suffered a fall at her home. She was admitted to the hospital for observation, as she had some bruises and difficulty ambulating. Coagulation parameters were within normal range, and the platelet count was stable. As part of the assessment in the ED, she underwent a CT scan of the abdomen and pelvis. This demonstrated a possible mass in the right inguinal region of about 4.5 cm, suggestive of bulky lymphadenopathy. No other lymphadenopathy or splenomegaly was present. Therefore, and with the change in the blood counts, the possibility of a hematologic malignancy appeared more likely.
A biopsy was pursued of this mass, and to the patient’s relief, it was found to be an organizing hematoma, which was also infected. She was treated with antibiotics and physical therapy, and her condition improved back to her baseline. She felt entirely well, and other than exercising neutropenic precautions, was leading an active daily life.
However, the issue of the pancytopenia persisted. Furthermore, knowing her history with the rheumatoid arthritis, the clinicians were concerned about when the next flare in her disease may be, and what treatment options would be appropriate at that time. A bone marrow biopsy was again discussed at that time, and given these considerations, she consented to having the procedure performed.
The patient tolerated the bone marrow biopsy extremely well. By the next morning, a call was received from hematopathology, that preliminary review showed acute myelogenous leukemia. Final pathology revealed deletion of chromosome 7q, as well as large granular lymphocytosis on part of the specimen. Blast count was 35% (on the core biopsy and by flow cytometry), and overall cellularity was 30%. Dysplastic forms in megakaryocytes were also observed.
Put together, the results were suggestive of antecedent myelodysplasia evolving to acute myelogenous leukemia (AML). The element of large granular lymphocyte leukemia was likely secondary to the rheumatoid arthritis.
The prognosis of AML was reviewed with the patient and her family, along with possible treatment options. After a prolonged discussion, and in spite of initially being hesitant about undergoing the bone marrow biopsy, she stated that she was interested in pursuing some form of therapy. Her main caveat, understandably, was that she did not want to experience too many side effects, while hoping to concurrently avoid hospitalizations. At this point, her ECOG performance status was 1.
Among the therapeutic strategies reviewed included hypomethylating agents such as 5-azacitadine; clofarabine; induction chemotherapy (modified for age); as well as best supportive care approaches such as transfusions and count control, among others. The patient ultimately opted for treatment with 5-azacitadine.
The patient tolerated the first cycle of 5-azacitidine (subcutaneously) treatment quite well. She had a decreased energy level for about 5 days, and also developed constipation controlled with laxatives. In the week following cycle 1, she required 1 unit of packed red blood cells for symptomatic anemia at a hemoglobin of 7.7 gm/dL.
Remarkably, about 3 weeks after treatment, her blood counts improved impressively. WBC count was 4,400 (88.7% neutrophils); Hgb 9.7 gm/dL; and platelets 264,000 /mL. MCV has normalized to 93.4. The patient is feeling well, and is beginning cycle 2 of treatment. Although she still faces a very serious malignancy, she expressed her happiness that she was tolerating the therapy generally well, along with her clinical improvement, while maintaining her quality of life.
Discussion
A number of research efforts have taken place over the past few years regarding the treatment of AML in the elderly. Even in younger, fit patients side effects and therapy-related mortality can be high. Therefore, in a case such as the current one, which involved an octogenarian, cytarabine-based standard induction therapy, even at modified doses, was not recommended. In this patient’s case, she also wanted to avoid hospitalizations and preserve quality of life, which would be nearly impossible with such a line of treatment.
Fortunately, other treatments have come to the fore as viable options. For example, in the NCCN guidelines for treatment suggestions, regimens include decitabine; 5-azacitadine; low-dose cytarabine; and clofarabine. In the case at hand, cytogenetics showed deletion of 7q (intermediate risk), along with a hypocellular marrow with dysplastic forms in certain cell lineages, suggestive of antecedent myelodysplasia. In line with this, an important phase 3 trial that was performed, and published in Lancet Oncology in 2009, compared 5-azacitdine with a physician’s choice of “conventional care regimens.” In the study, a total of 358 patients were enrolled. “Conventional care” was comprised of “intensive” induction chemotherapy, low-dose cytarabine, and best supportive care. The patients had an International Prognostic Scoring System result of either intermediate-2 or high-risk. At least 30% to 35% of patients in each of the arms had over 20% blasts, defining them as AML. After a median follow up of 21.1 months, there was a significant advantage in survival for the azacitidine arm, at 24.5 vs. 15.0 months (HR 0.58, 95% CI: 0.43-0.77, log-rank p = 0.0001).
Decitabine has also induced complete responses in older patients with AML, in up to 30% of individuals, although without a definite survival advantage. Another chemotherapeutic drug, clofarabine has also shown good response data, although in general, therapy is somewhat more difficult to tolerate than the hypomethylating agents. Data such as these led to the selection of 5-azacitadine in the patient discussed in the case.
In summary, there is a growing body of literature about the treatment of older patients with acute myelogenous leukemia. Therapy has to be carefully selected, but can yield good responses, while preserving quality of life in this potentially challenging population of patients.
Amit Mehta, MD, is an attending physician at Regional Cancer Care in Durham, N.C., and is a member of the HemOnc Today Editorial Board. Disclosure: Dr. Mehta reports no relevant financial disclosures.
For more information:
- Cashen AF. Journal of Clinical Oncology 2010 Feb 1;28(4):556-61. Epub 2009 Dec 21.
- Erba HP. Journal of Clinical Oncology 27 (15S): Abstract 7062, 2009.
- Fenaux P. Lancet Oncology. 2009 Mar;10(3):223-32. Epub 2009 Feb 21.
- O’Brien S. J Natl Compr Canc Netw. 2009 Oct;7(9):984-1023. No abstract available.