This month Jonathan E. Kolitz, MD, discusses treating a patient with acute lymphocytic leukemia who is of advanced age.
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An otherwise fit 92-year-old who presented with pancytopenia was diagnosed with Philadelphia chromosome negative (Ph-) B-cell acute lymphocytic leukemia (B-ALL). I am worried about using anthracycline-based chemotherapy because of his age. I am considering vincristine plus prednisone (low-intensity therapy). Would you consider alternative therapies (e.g., inotuzumab ozogamicin or blinatumomab) in the upfront setting?
Managing an advanced age patient with ALL is challenging. Less than 10 percent of patients with ALL over age 60 are long survivors. There may be no long survivors among patients older than 80 to 90 years. Older patients with ALL are more likely to have comorbidities and adverse cytogenetic findings. The Ph chromosome is present in more than 40 percent of older patients with ALL, and its presence provides a treatment option centered on tyrosine kinase inhibitor therapy, which may lead to meaningful palliation.
Options for this 92-year-old man with Ph- B-ALL are limited to careful use of active agents compatible with his physiologic state. Weekly vincristine for four weeks along with seven days of prednisone or dexamethasone could form the basis of an induction regimen. His age does not absolutely prevent use of an anthracycline if his cardiac function is normal. One may choose to give daunorubicin in the range of 30 mg/m2 on days one to three of the induction followed by pegfilgrastim or daily filgrastim starting on day four until count recovery. I would give prophylactic antibiotic therapy with a quinolone when the absolute neutrophil count is under 500/µL. Asparaginase should be avoided because of the risk of severe hepatotoxicity.
If remission is achieved, recurrence is likely to be rapid without further therapy. Several cycles of consolidation therapy are given in younger patients, using regimens like those described in CALGB 8811, BFM, or MRC UKALLXII/ECOG E2993. Given as prescribed, such therapies would most likely lead to prohibitive toxicities even in a fit 92-year-old. Consequently, these regimens can be adapted using significant reductions in dose or abbreviated schedules. Myeloid growth factors and prophylactic antibiotics should be used liberally. The MOAD regimen, originally published in 1982 – which uses escalating doses of methotrexate (“Capizzi methotrexate”) with asparaginase rescue, along with vincristine and dexamethasone – can be adapted for purposes of post-remission therapy, substituting leucovorin rescue for asparaginase as the methotrexate dose is escalated and reducing by at least 50 percent the exposure to dexamethasone. Intrathecal methotrexate and/or cytarabine should be given multiple times throughout post-remission therapy, as outlined in published trials. The value of prophylactic cranial radiation in this setting is unclear. If the patient is disease-free toward the end of consolidation therapy, it could be considered. Possible effects on cognition need to be assessed. Finally, if remission is sustained after a few rounds of consolidation therapy, maintenance therapy using POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) should be given for up to two years, as tolerated.
If the ALL blast population expresses CD20, rituximab could be given during induction and post-remission therapy. Its use with standard chemotherapy has been shown to improve event-free survival in CD20+ ALL (GRAALL-2005 study and others).
The use of the bispecific T-cell engager antibody blinatumomab or the immunotoxin inotuzumab in this setting is appealing; however, these agents are unavailable to previously untreated patients outside of clinical trials. Blinatumomab can have serious toxicities associated with cytokine release syndrome, including neurotoxicity and death. Treatment while in remission may reduce that risk. Inotuzumab can cause sinusoidal obstructive syndrome, a complication related to age, limiting the ability to use this agent in older patients. Clinical trials studying the use of these agents with chemotherapy and even the sequential use of these agents without chemotherapy are in progress or being developed. The findings could favorably affect future management of older patients with untreated ALL.
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NEXT MONTH'S CLINICAL DILEMMA
I have a patient at 37 weeks of her fourth pregnancy. She has a history of type 2A von Willebrand disease, requiring Humate-P replacement in the prior two deliveries and other bleeding occasions (epistaxis, hematuria, and heavy menses prior to last pregnancy, which required monthly doses of Humate-P 1,450 units). She will undergo vaginal induction delivery in two weeks. She weighs 161 pounds. Her current values are as follows: PT, PTT, and fibrinogen are normal; factor VIII is 96 percent; von Willebrand factor (vWF) antigen is 113 percent; and vWF activity is 34 percent. My recommendations include keeping activity level at 100 percent prior to delivery and three days postpartum, Humate-P 2,400 units 30 minutes prior to epidural, then the same dose every 12 hours for three days followed by Humate-P 1,450 units daily until hemostasis is achieved. Are my dosing recommendations correct?
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