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Friday, April 11, 2014

ONLINE FIRST: In APL, Warning about Differentiation Syndrome



NEW YORK -- ATRA/ATO is the new standard of care for non-high risk patients with acute promyelocytic leukemia (APL), and overall survival rates with the regimen are over 90 percent, even without chemotherapy. But the incidence of early death during induction therapy is still high, and the development of APL differentiation syndrome, although rare, can be fatal if not treated immediately upon suspicion.


APL is clearly one of our success stories,” said Charles Schiffer, MD, Professor of Medicine and Oncology, and Interim Chair of the Department of Oncology at Karmanos Cancer Institute in Detroit, moderator of a session on leukemia here at the recent International Congress on Hematologic Malignancies.


 In introducing Martin Tallman, MD, Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, Schiffer said Tallman would describe how he treats APL, “but also remind us what not to do, because the greater tragedy is when you mess things up in someone who has a potential 80 or 90 percent cure rate.”


Tallman said the complete remission rate in general is indeed approximately 90 percent among patients with APL, and that ATRA/ATO – all-trans retinoic acid and arsenic trioxide – is the standard of care. But among that 10 percent who do not have a complete remission, approximately 60 to 70 percent will die from intracerebral or gastrointestinal bleeding, and 30 percent from infection.


In addition, that 90 percent complete remission rate is from large cooperative group trials, whereas population-based studies that include every patient diagnosed show an early mortality rate of 20 to 30 percent – for example, this one for which he was senior author (Park et al: Blood 2011;118: 1248-1254). Early death rate, and not relapse, has emerged as the single most important limitation to cure for the majority of patients,” Tallman said.


He reviewed the basics of APL:

·    It comprises 10 to 15 percent of adult acute myeloid leukemia (20-30 percent in Hispanics);

·    The overwhelming majority of patients with APL present with leukopenia;

·    APL is associated with life-threatening coagulopathy;

·    Almost every patient with APL has a (15;17) translocation;

·    APL cells are uniquely sensitive to anthracycline; and

·    Every APL patient has the PML-RAR-alpha fusion transcript associated with the t(15;17).


But the most distinguishing features, he said, are that these cells undergo differentiation to mature granulocytes with ATRA, and apoptosis with ATO. It's interesting that at a time when in most hematologic malignancies researchers are searching for better prognostic factors, and molecular prognostic factors are becoming more important, in fact the opposite is occurring in APL,” Tallman said.


We have as the major prognostic factor simply the peripheral white blood cell count,” and age is the other major prognostic factor. Platelet count is not seen today as critical, he said, and FLT3-ITD status has no prognostic importance.


Reduce Early Death with Early ATRA

It became apparent very early in the experience with ATRA that it reverses coagulopathy quite quickly -- in a median of about four days, Tallman noted.


Then why is the early death rate still a problem, since ATRA has been available for almost 20 years? And will early administration of ATRA reduce the death rate from bleeding? Time to ATRA administration appears to be a major reason.


In a study of time of ATRA administration for which Tallman was senior author (Altman et al: Leukemia Res 2012; 37: 1004-1009), ATRA was ordered for only 32 percent of patients on the day APL was suspected, in 33 percent one day after APL was suspected, and almost 20 percent of patients two or more days after. Since ATRA was received by 90 percent of patients on the day it was ordered, the critical delay was not in the length of time from ordering to time of administration but rather in ordering the drug, Tallman explained.


And there is no doubt that ATRA delay is related to risk of bleeding, he said: It is now recommended that ATRA be started at the first suspicion of the disease, based on clinical history and review of the peripheral blood smear, but before a bone marrow [biopsy] is done and before the diagnosis is confirmed. Many people now feel that ATRA should be administered in the emergency room, so it's important that ER doctors recognize APL.”


Tallman described a unique complication to ATRA exposure, the APL differentiation syndrome, which also calls for immediate treatment. Before diagnosis of the syndrome is even established, maintain vigilance, and give dexamethasone at 10 mg twice daily at the earliest symptom or sign, he said.


Stop ATRA or ATO if the syndrome is severe, and then resume at the resolution of all symptoms and signs under the cover of steroids.”


Evolution in Induction Strategies

There has been an evolution in induction therapy away from chemotherapy and toward the administration of ATRA and ATO, Tallman said, citing no less than six major cooperative studies using ATRA with little or no chemotherapy, showing complete remission rates of 89 to 100 percent, and overall survival rates of 89 to 99 percent.


He cited another study, which he said pointed to a regimen that could be used practically, outside the context of a clinical trial: Patients in the Australasian Leukemia and Lymphoma Group APML4 study (Iland et al: Blood; 2012;120: 1570-1580) received ATRA/ATO, and idarubicin, along with prophylactic prednisone for induction, while consolidation consisted of only two courses of therapy with ATRA/ATO, with no additional chemotherapy. Maintenance was ATRA on days 1-14 of a 90-day cycle, and 6-mercaptopurine and low-dose methotrexate on days 15-90, repeating the cycle for two years. Patients with low-, intermediate-, and high-risk disease had two-year relapse-free rates of 100, 98, and 92 percent, respectively.


Another trial, the GIMEMA/SAL/AMLSG-APL0406 study, also showed very successful results, with little or no chemotherapy for low-risk patients: Lo-Coco F et al. N Engl J Med 2013; 369:111-121  OT 8/25/13 issue). The overall survival rate at approximately four years was 98.7 percent for patients receiving ATRA/ATO.


Tallman said he enrolls patients on a clinical trial for induction if one is available. Otherwise he uses ATRA/ATO for low-risk patients, adding idarubicin for high-risk patients as in the Australian study. ATRA/idarubicin for both low- and high-risk patients is still a reasonable induction approach as well,” he said.


And, he recommends intrathecal central nervous system prophylaxis for high-risk patients.


‘Tricks’ That Work

Tallman offered his “tricks of the trade” in APL induction:


First, he said, there is no evidence that therapy need be modified based on additional cytogenetic abnormalities, whether the APL is therapy-related, FLT3 mutations, CD56, PML isoform, or morphology.


And there is no need for a bone marrow biopsy on day 14, he said, and it may not even be needed once a patient achieves complete remission. If a patient survives induction, there is no primary resistance in this disease. Everybody achieves a remission if they survive induction. And there is no prognostic importance of any cytogenetic abnormality or molecular findings, when first remission is achieved. So I'm not sure we need to be doing any complete remission bone marrow. ”

He recommends aggressive platelet transfusion and fibrinogen replacement, but said a central venous catheter should not be placed. Leukapheresis is generally not recommended, and myeloid growth factors are not needed.


He reiterated the need to watch for APL differentiation syndrome and to give dexamethasone to high-risk patients or at the earliest sign or symptom, such as shortness of breath, cough, or pleural effusion.


An exciting development in the field, he said, is the promise of an oral arsenic for treatment of APL. ATRA is administered orally. “I think an all-oral regimen for APL is not far in the future,” he said.