VIEWPOINTS maintenance therapy with CC-486 ( hazard ratio [ HR ] = 0.69 ; FIGURE ). Relapse-free survival ( RFS ) also was prolonged ( HR = 0.65 ). The survival benefit with CC- 486 was independent of relevant prognostic factors , including cytogenetic risk ( intermediate vs . poor ) and number of consolidation courses . While the improvement in OS is noteworthy , putting this in context and describing the applicable patient population vis-à-vis the FDA approval label is necessary .
First , while the optimal number of cycles of consolidation chemotherapy in the treatment of AML is debatable , most experts would agree it is more than one , although tolerability of intensive consolidation in older patients may limit this . Thus , the question that was answered by QUAZAR was : Is CC-486 superior to placebo for patients who receive induction plus a median of one cycle of consolidation ? The FDA label could be construed to reflect an incomplete intensive therapy schedule , but no strict definition of the term “ not able to complete intensive curative therapy ” is actually provided in the prescribing information . So , the question of whether CC-486 is superior to placebo after conclusion of ” full ” consolidation ( with likely greater curative potential ) remains unanswered .
Younger patients with AML who received parenteral azacitidine maintenance in CALGB 10503 had no benefit over placebo . 7 By contrast , HOVON97 was an attempt to use parenteral azacitidine in older patients who received at least 2 cycles of consolidation chemotherapy . This led to a promising improvement in disease-free survival , but not OS . 8 Whether CC-486 would have fared better in these patients is intriguing , as is an argument that parenteral azacitidine might have yielded similar results to QUAZAR if more limited consolidation were offered in HOVON97 .
Second , CC-486 did improve median OS and median relapse-free survival compared with placebo , but in the end , “ All roads lead to Rome .” The survival curves appear to converge several months beyond the median follow-up , with the caveat of censoring and small numbers to be clarified when further data are published . As such , it is plausible that the intervention did not increase cure rates , but rather delayed relapse and also death . CC-486 was well tolerated with only 5 % of patients discontinuing therapy for treatment-related adverse events ( predominantly gastrointestinal ) and an impressive median number of 12 cycles administered ( compared with 6 for placebo ).
Finally , QUAZAR was designed and recruited prior to the approval of targeted induction therapies including gemtuzumab ozogamicin , novel delivery technology for chemotherapy ( such as CPX-351 ), and the use of venetoclax in AML . In addition , a high ( and growing ) proportion of patients with AML proceed to transplant rather than consolidation and CC- 486 was not studied as a bridge to transplant . Thus , the QUAZAR trial data clearly support a benefit for CC-486 maintenance in a selected cohort of AML patients , but its role in the era of recent drug approvals for AML needs further evaluation . ●
References 1 . Rashidi A , Walter RB , Tallman MS , et al . Maintenance therapy in acute myeloid leukemia : an evidence-based review of randomized trials . Blood . 2016 ; 128:763-773 .
2 . Savona MR , Odenike O , Amrein P , et al . A phase 1 dose-escalation study of ASTX727 , a combination of the oral cytidine deaminase inhibitor ( CDAi ) E7727 with oral decitabine , in subjects with myelodysplastic syndromes ( MDS ). Lancet Haematol . 2019 ; 6:194-203 .
3 . Garcia-Manero G , Griffiths E , Steensma D , et al . Oral cedazuridine / decitabine : a phase 2 , multicenter pharmacokinetic / pharmacodynamic randomized , crossover study in MDS and CMML . Blood . 2020 ; 136:674-683 .
4 . Garcia-Manero G , Gore SD , Cogle C , et al . Phase I study of oral azacitidine in myelodysplastic syndromes , chronic myelomonocytic leukemia , and acute myeloid leukemia . J Clin Oncol . 2011 ; 29:2521-2527 .
5 . Laille E , Savona MR , Scott BL , et al . Pharmacokinetics of different formulations of oral azacitidine ( CC-486 ) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies . J Clin Pharmacol . 2014 ; 54:630-639 .
6 . Garcia-Manero G , Gore SD , Kambhampati S , et al . Efficacy and safety of extended schedules of CC-486 ( oral azacitidine ) in patients with lower risk myelodysplastic syndromes . Leukemia . 2016 ; 30:889-896 .
7 . Blum W , Sanford BL , Klisovic R , et al . Maintenance therapy with decitabine in younger patients with acute myeloid leukemia in first remission : a phase II Cancer and Leukemia Group B study ( CALB 10503 ). Leukemia . 2017 ; 31:34-39 .
8 . Huls G , Chitu D , Havelange V , et al . Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients . Blood . 2019 ; 133:1457-1464 .
You Make the Call : Readers ’ Response
We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”
To see how the expert responded , turn to page 18 .
CLINICAL DILEMMA :
I have a patient with newly diagnosed chronic lymphocytic leukemia ( CLL ) who has normal cytogenetics . The presenting features were fever and hypoxia that led to 2 weeks of hospitalization ; bronchoscopy revealed pneumocystis pneumonia . The patient is HIV negative and is now doing well without any typical criteria for CLL treatment . He has received intravenous immune globulin ( IVIG ) twice for IgG level of 200 mg / dL . Is hypogammaglobulinemia alone an indication for treatment for CLL , in the absence of other symptoms or cytopenias ?
I would not typically treat CLL for hypogammaglobulinemia . I would continue on IVIG with the expectation that the Ig levels will improve with monthly infusions .
Yes , should proceed to treatment .
Myron Bednar , MD Flemington , NJ
I would strongly favor treating this patient for CLL since he had pneumocystis pneumonia infection and has a functional defect in humoral immunity . His history of prior infection portends high risk for future infections . Although he does not have cytopenias , the defect in B cell production of IgG is due to the underlying lymphoproliferative disorder and requires treatment .
Shyam A . Patel , MD , PhD Worcester , MA
It depends on the patient ’ s immune status . If the patient is clinically symptomatic with recurrent infections that are affecting daily life , then I do think it ’ s appropriate to treat .
Deborah Vaz , MBBS Pretoria , South Africa
No . Treatment of CLL usually does not help to ameliorate the hypogammaglobulinemia , even if a complete remission is achieved . If CLL with hypogammaglobulinemia is complicated by repeated infections , Ig substitution may lead to lesser infections . I do not know whether Ig substitution confers protection against pneumocystis in particular . I suspect it will not help because immunity to that particular pathogen is based on cellular defense mechanisms .
Christian Rudolph , MD Eberswalde , Germany
I would continue the immune globulin and would not start treatment for the leukemia .
Joseph R . Holahan , MD San Antonio , TX
William Robinson , MD , PhD Aurora , CO
I would infuse IVIG to keep the IgG level at 600 mg / dL or higher , treat infections , and watch . If the patient has repeated infections despite keeping IgG at a higher level , I would treat the CLL .
No , it is not an indication for treatment .
Phillip Periman , MD Amarillo , TX
Márk Plander , MD , PhD Szombathely , Hungary
See more reader responses at ashclinicalnews . org / you-make-the-call .
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