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A 41-year-old woman with a transforming lymphoma
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In the May issue this year, I presented a case of a patient found to have follicular lymphoma, who had initially presented with unusual systemic manifestations. The current case will be a follow-up of that particular patient, who suffered from a dramatic transformation to one of the most lethal hematological malignancies.
To summarize the previous presentation, the patient is a 41-year old woman with an unremarkable past medical history, who was initially referred for a consultation for severe thrombocytopenia in concert with lower back and bilateral leg pains. Evaluation was notable for the patient having had mesenteric and retroperitoneal lymphadenopathy (1.5 cm to 2 cm in diameter) on a CT abdomen/pelvis 4 years prior (performed for abdominal pain), which was not pursued further at that time. A repeat CT abdomen/pelvis this year showed persistent adenopathy, along with splenomegaly.
A subsequent bone marrow aspiration and biopsy demonstrated follicular lymphoma. The marrow had a 100% cellularity, with Ki-67 of 10%. Flow cytometry showed a large CD19 and CD10-positive B-cell population that featured lambda light chain restriction. Cytogenetics revealed t(14;18) and del(6q).
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At this point in her course, she was having persistent pain requiring narcotic analgesia, had a rising white blood cell (WBC) count, and had uterine bleeding requiring transfusions (secondary to lymphomatous involvement of the uterus). As such, she was treated aggressively to elicit a rapid response and obtain disease control, via systemic chemotherapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone. She tolerated treatment well, with robust tumor lysis, and complete resolution of her symptoms after chemotherapy. After this first cycle of chemotherapy, she had a recovering complete blood count (CBC), with platelets to 39,000 and WBC count to 4,600.
Complication of symptoms
She seemed to be doing well, when about 5 days before her next cycle of chemotherapy, she again began to have pain in the back and the legs, had nausea, and felt generally weak. She came for an outpatient office visit, and based on her evaluation, was admitted to the hospital. There, blood work revealed a recurrent leukocytosis to 21,800 /mcL, with peripheral blood lymphoma cells noted. Serum creatinine was also elevated at 1.5 mg/dL. Later in the day, the creatinine rose to 4 mg/dL, and the serum lactic dehydrogenase (LDH) was found to be 15,543 U/L. The uric acid was markedly elevated at 22.7. She was treated with IV fluids to alkalinize the urine, in preparation for urgent chemotherapy. Nephrology consultation was requested due to the possibility of dialysis for severe tumor lysis syndrome.
However, by the next morning, the creatinine rose to 7.5 mg/dL, and the potassium to 7.2. She was expeditiously begun on dialysis, and also received rasburicase for the severe hyperuricemia. The LDH rose dramatically to 34,281 U/L before the start of chemotherapy.
Unexpected findings
This clinical picture was clearly unexpected for follicular lymphoma. Repeat pathology demonstrated that the follicular lymphoma cell population had acquired a MYC gene rearrangement. Importantly, in addition, peripheral blood flow cytometric analysis showed that two distinct cell populations were present. Firstly, 50% of the cells were blast cells, expressing CD10, CD19, and TdT. There was no expression of surface immunoglobulins, myeloperoxidase or CD3. Secondly, there was a population comprising 2% of the cells, featuring CD10 and a monoclonal lambda-restricted surface immunoglobulin. Cytogenetics were negative by polymerase chain reaction for a BCR ABL translocation.
Put together, the patient originally had a follicular lymphoma, which transformed into acute lymphoblastic leukemia/lymphoma. The follicular lymphoma behaved very aggressively, likely due to the presence of a MYC rearrangement, and this combination of features defines the lymphoma as a “double-hit” lymphoma. These are generally very aggressive malignancies, and fall into the 2008 WHO classification as a “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma.” On top of that, the lymphoma had transformed to a precursor B-cell lymphoblastic lymphoma/leukemia.
The patient was urgently begun on systemic chemotherapy with HyperCVAD. She required dialysis during the first few days of treatment, but responded very well. Her renal function stabilized and began to slowly improve, and she became appropriately pancytopenic after Cycle 1A. The LDH began to steadily decrease, and although it did not quite normalize, was down to around 300 U/L.
However, about 4 days before the patient was scheduled to begin Cycle 1B, she had an acute change in mental status. The patient was found to be very somnolent, and although she was arousable, she was having visual and auditory hallucinations. The LDH and WBC count began to rise, and therefore was begun on Cycle 1B early to achieve response. MRI of the brain showed subtle changes suggestive of possible central nervous system (CNS) involvement, although cerebro-spinal fluid (CSF) analysis was negative for malignant cells. Along with intrathecal chemotherapy with HyperCVAD, the patient began to respond to treatment. Her mental status improved in about 5 days, and the patient again stabilized.
She was planned for discharge, when she again had the development of altered mental status. Immediate imaging of the brain revealed vasogenic edema, and small ventricles suggestive of elevated intraventricular pressure, but no clear new findings. The patient rapidly deteriorated and became unresponsive. She was intubated and brought to the ICU. The right pupil became fixed and dilated. Exam was also significant for a fever, and she was begun on broad-spectrum antimicrobial therapy; various bacterial and viral studies were negative. CSF analysis confirmed an elevated intraventricular pressure; neurosurgery was arranged for a ventriculostomy system to accurately monitor cerebral perfusion pressures and intracranial pressures.
It was not clear if the patient’s neurologic status was secondary to chemotherapy toxicity, perhaps from high-dose methotrexate with Cycle 1B of HyperCVAD, or from CNS involvement of leukemia. After multiple CSF analyses, flow cytometry from the CSF returned positive for leukemia. After extensive discussions with the patient’s family, Cycle 2A of HyperCVAD was started in hopes of eliciting a response to stabilize the situation. Unfortunately, the patient’s clinical status did not improve and worsened further with the onset of seizures. After further conversations with the family, they elected for comfort care measures, and the patient was terminally extubated. She passed away shortly thereafter.
Discussion
For all the clinicians involved, the most striking aspect of this sad case was the incredible pace of growth of the lymphoma. Before the patient could even make it to her next scheduled cycles of treatment, even with a regimen as aggressive as HyperCVAD, the WBC count and LDH would again begin to rise, and the patient would have multiple serious symptoms moving her into a critical status.
Double-hit (DH) lymphomas are a fairly new entity in the realm of hematologic malignancies. These are now known to be among the most aggressive of lymphomas, with a rapid growth rate, potential multi system involvement, and often a poor response to treatment. Therefore, DH lymphomas are often associated with poor prognostic variables, and standard lymphoma treatments, such as R-CHOP or R-CVP, are generally inadequate. This is believed to be largely driven by the MYC gene rearrangement in these tumors, or perhaps the synergistic action of the MYC and BCL2 seen in these tumors.
Clinically, these patients can often have the involvement of multiple organ systems. Several of these were seen in this unfortunate patient’s case. Other than the bone marrow, the CNS can be involved, along with the uterus, muscle and skin. The optimal treatment regimen is unknown. It does appear to be clear that standard regimens such as R-CHOP are essentially futile in the long term for this malignancy, with survivals less than 1 year and very few remissions. As such, a more aggressive regimen was employed for this patient, with HyperCVAD selected also due to the transformation to acute lymphoblastic lymphoma/leukemia. For precursor B-cell malignancies, such as ALL, the response rates are quite high generally, up to more than 90%. However, these rates were likely tempered by the underlying genetics of the antecedent malignancy of a DH lymphoma.
Perhaps the only thing more dramatic than the clinical aggressiveness of the lymphoma was the tremendous support and bravery of the patient’s family in the face of such a situation. Their strength will not soon be forgotten.
In conclusion, this case reinforces the overriding importance of cytogenetics in driving the aggressiveness of a hematologic malignancy. As the understanding of DH lymphomas and transformation malignancies matures, hopefully translational research can offer these patients greater hope for successful treatment.
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 has no relevant financial disclosures to report.
For more information:
- Armitage JO. Non-Hodgkin Lymphomas, 2nd ed. New York: Lippincott, Williams, and Wilkins; 2010.
- Aukema SM. Blood. 2011; 117:2319-2331.
- Hasserjian RP. J Hematopathol 2: 89-95. 2009; 2: 89-95.
- Thomas DA. Blood. 2004; 104:1624-1630.