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Adrienne A. Phillips et al.
Table 3. Most common* treatment-related adverse events.
During randomization After crossover Mogamulizumab Investigator’s choice Mogamulizumab
All grades
8 (44)
Adverse event
All grades Grade ≥3 All grades Grade ≥3 22 (47) 4 (9) 0 0
Grade ≥3 1 (6)
(n=47) (n=24) (n=18)
Non-hematologic
Infusion-related reaction
Drugeruption 9(19) 0 0 0
1(6)
4(22)
3(13) 1(4) 1(6) 0 4(17) 1(4) 0 0 3(13) 1(4) 0 0 ALTincreased 2(4) 1(2) 2(8) 1(4) 0 0
Pyrexia 3(6) 0 Nausea 2(4) 0 Headache 2(4) 0
Diarrhea 0 0 4(17) 0 2(11) Fatigue 2(4) 0 2(8) 0 2(11) Constipation 0 0 3(13) 0 1(6) ASTincreased 2(4) 1(2) 2(8) 1(4) 0
0 1(6) 0
0
0
0
0
0
0
0 1(6) 0
2 (11) 1 (6)
Vomiting 0
0
0
0
0
0
0
0
5 (11)
1 (2) 4 (9)
3(13) 2(8) 1 (4) 2 (8) 0
0
0
3 (13)
6 (25) 5 (21)
0 0 0 0 0 0 0 0
0
4 (17)
0
0
2 (11) 0 2(11) 2(11) 2(11) 2 (11)
3 (17) 1(6)
Weightdecreased
Decreased appetite
Mucosal inflammation
Tachycardia 0 Asthenia 0 Dyspnea 0
Infections†
Hematologic
Neutropenia
Thrombocytopenia
7 (15)
2 (4) 6 (13)
1(2) 2 (4) 0
Anemia 5(11) 1(2) 1(4) 0 1(6) 1(6)
Data are given as n (%) unless otherwise stated. ALT: alanine aminotransferase; AST: aspartate aminotransferase. *Most common all grade adverse events that occurred in ≥5% of patients in either randomized group or ≥2 patients during crossover. †Incidence reported is for infections overall. Specific infections reported by ≤2 patients were: lower res- piratory infection, oral candidiasis, cellulitis and neutropenic sepsis for investigator’s choice regimens; lower respiratory infection, oral candidiasis, pneumonia, breast abscess, candidiasis, viral conjunctivitis, Escherichia urinary tract infection, oropharyngeal candidiasis, pneumocystis jiroveci pneumonia and urosepsis for mogamulizumab in random- ized period; lower respiratory infection and upper respiratory infection for mogamulizumab in crossover period.
Leukopenia 3(6) 0 0 0 0 0
nostic factors at baseline, including older age, higher ECOG performance status, and greater bone marrow involvement than in the Japanese study. The aggressive- ness of the disease in the patients on this study was reflected in the high number of subjects (65%) that com- pleted ≤1 treatment cycle. Lastly, our study enrolled a more ethnically diverse patient population, and differ- ences in disease biology, clinical presentation, and response to treatment have been suggested in Japanese patients compared to those in other regions,15,26 although this has not been studied prospectively.
The Shimoyama classification of ATL12 and recom- mended response criteria for ATL25 have been useful for the standardization and comparison of outcomes of Japanese patients with those in the other countries. However, a number of pitfalls in these schema have been reported27 and these were observed in this trial. Complex presentations with leukemic, lymphomatous, and skin compartments may complicate assessment, as disease control in one or more compartments, even alongside an increase in another compartment, may result in significant clinical improvement in a patient, although the patient technically meets progression criteria as the overall response.
Protocol-defined progression was based on Tsukasaki criteria for composite scoring using data from all disease compartments (blood, skin, lymph nodes, extranodal masses, liver/spleen, and bone marrow), which are often involved to various degrees in a single patient and may have led to the clinical benefit being underestimated. In an aggressive, rapidly progressive disease such as ATL, clinical benefit may be apparent to the treating physician, and remains important even if a later blinded composite response is PD. Notable responses were observed in this study in peripheral blood (54%, all with CR) and skin (44%), and several subjects described were considered to be benefiting from mogamulizumab besides those repre- sented in the cORR data.
There is no approved ATL treatment outside Japan. Investigator’s choice of chemotherapy regimen in the trial was between GemOx, pralatrexate, and DHAP, with almost all (87%) allocated to GemOx. These regimens were most commonly used for the treatment of relapsed/refractory ATL in the countries where this study was conducted, although there is virtually no published evidence of clinical efficacy. Other studies or series have indicated little evidence of clinical efficacy in relapsed/refractory ATL with regimens such as cladrib-
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haematologica | 2019; 104(5)