PracticeUpdate: Haematology & Oncology

HAEMATOLOGY

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Extramedullary disease in adult acute myeloid leukaemia is common but lacks independent significance Comment by Isabel Cunningham, MD T he cure of leukaemia requires eradica- tion of total body leukaemia burden, in both bone marrow and non-marrow Extramedullary disease in adult acute myeloid leukemia is common but lacks independent significance: analysis of patients in ECOG-ACRIN Cancer Research Group Trials, 1980–2008 Journal of Clinical Oncology Take-home message

in leukaemia cases confirm that clinical as- sessment vastly underestimates the extent of leukaemic involvement, as has been known for decades from autopsy series. Calling a tumour “isolated” without total body confirma- tion allows occult disease to grow, spread, and ultimately contaminate marrow with resistant disease. Scans would be especially valuable in identifying reasons for minimal residual dis- ease and refractory marrows and in decreasing the persistently high risk of post-transplant re- lapse. An approach employing the technology, routine in treating patients with every other cancer, and leukaemic tumour eradication by surgery and/or RT, is deserved by leukaemia patients and could finally decrease the high relapse rate after regimens aimed at cure.

organs. Leukaemic tumours are invasive, metastatic, and typically only transiently sensitive to drugs designed to treat marrow leukaemia. They may grow silently to very large size (>10 cm) and kill patients even when mar- row is in remission. This article enumerates only cases found on physical examination and regional evaluation, ignoring possible occult involvement of lungs, pelvic organs, GI tract, kidney etc, and includes liver and spleen not traditionally considered extramedullary sites in the absence of focal lesions. Most lesions were not pathologically confirmed. For these reasons, its conclusions and incidences have little educational value. We can do better. PET/CT scans, used in leukaemia since 2004, and gallium scans since the early 1970s, make it possible to determine extent of disease in leukaemia. The available 124 reports of scans

• The authors looked at the incidence and clinical implications for extramedullary disease (EMD), a common comorbid condition in patients with acute myeloid leukemia (AML). The overall incidence of EMD was 23.7% in a cohort of newly diagnosed AML patients (N = 3240). The presence of any EMD was associated with a shorter overall survival (P = 0.005). In adjusted multivariate analysis that takes known prognostic factors into account, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. • The study authors conclude that EMD is relatively common, but not an independent prog- nostic factor in AML. They suggest that AML treatment decisions should be based on the presence of recognized AML prognostic factors, and not on the presence of EMD. Abstract site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites.

Dr Cunnigham is Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York.

PURPOSE Extramedullary disease (EMD) at di- agnosis in patients with acute myeloid leuke- mia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in con- secutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. METHODS Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. RESULTS Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one

The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD (P = 0.005), skin involvement (P = 0.002), spleen (P < 0.001), and liver (P < 0.001), but not CNS (P = 0.34), nodal involvement (P = 0.94), and gingival hypertrophy (P = 0.24), was associated with a shorter overall survival. In contrast, in multivari- able analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an inde- pendent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, ir- respective of the presence of EMD. J Clin Oncol 2016 Aug 29;[Epub ahead of print], Ganzel C, Manola J, Douer D, et al.

Haematology practice implications: newHodgkin’s lymphoma research INTERVIEW WITH ANDRE GOY, MD Dr Goy, Chief of Lymphoma at the John Theurer Cancer Center,

Hackensack University Medical Center (United States) discusses the latest clinical trial ad- vances in Hodgkin’s lymphoma, including on nivolumab with ABVD or brentuximab and targeting biomarkers in order to use immuno- therapy better.

Reduced risk of relapse following cord-blood transplantation in patients with minimal residual disease Comment by Isabel Cunningham, MD

very key variable in every transplant study about relapse, especially from centres that receive patients from everywhere, are time between last chemo and transplant and the time to acquire a suitable donor. These data were not provided in this paper, though it concludes with a comment that time to transplant is a critical determinant in transplant success.

diseases (AML, ALL, MDS), differ- ent protocols selected by “clinical priority” with differing conditioning and GvHD regimens, with either marrow or blood cells from three different types of donors, make it challenging to draw useful conclu- sions from the results. Determining relapse rate is always difficult when there is appreciable early mortal- ity, as there was in these groups. A

pre-transplant residual disease, a known poor prognostic factor, with graft source. It reports inter- esting findings about double-cord transplants, the source which has enabled more patients to find com- patible donors, notably non-whites (54% of their cord group). How- ever, the large number of variables in the treatments of 582 patients over 9 years, including different

“Conclusions (to) be made with caution”, the authors’ advice near the end of this paper, makes one question why they published theirs. This work is an effort to correlate

Determining relapse rate is always difficult when there is appreciable early mortality, as there was in these groups.

Cord-blood transplantation in patients withminimal residual disease The New England Journal of Medicine Take-home message

1.69; 95% CI, 0.94 to 3.02; P=0.08). Among patients without minimal residual disease, the hazard ratios were lower (hazard ratio in the HLA-mismatched group, 1.36; 95% CI, 0.76 to 2.46; P=0.30; hazard ratio in the HLA-matched group, 0.78; 95% CI, 0.48 to 1.28; P=0.33). The risk of relapse among patients with minimal residual disease was significantly higher in the two unrelated-donor groups than in the cord-blood group (hazard ratio in the HLA-mismatched group, 3.01; 95% CI, 1.22 to 7.38; P=0.02; hazard ratio in the HLA-matched group, 2.92; 95% CI, 1.34 to 6.35; P=0.007). Among patients without minimal residual disease, the magnitude of these associations was lower (hazard ratio in the HLA-mismatched group, 1.28; 95% CI, 0.51 to 3.25; P=0.60; hazard ratio in the HLA-matched group, 1.30; 95% CI, 0.65 to 2.58; P=0.46). CONCLUSIONS Our data suggest that among patients with pretrans- plantation minimal residual disease, the probability of overall survival after receipt of a transplant from a cord-blood donor was at least as favorable as that after receipt of a transplant from an HLA-matched unrelated donor and was significantly higher than the probability after receipt of a transplant from an HLA-mismatched unrelated donor. Furthermore, the probability of relapse was lower in the cord-blood group than in either of the other groups. N Engl J Med 2016;375:944-953, Milano F, Gooley T, Wood B, et al.

• This was a single-center, retrospective study including 582 patients with acute leukemia or myelodysplastic syndrome in which the authors compared outcomes for patients who underwent myeloablative hematopoietic cell transplant from either an unrelated cord-blood donor, an HLA-matched unrelated donor, or an HLA-mismatched unrelated donor. In patients without minimal residual disease (MRD-negative) at the time of transplant, there was no significant difference in overall or relapse-free survival among patients who received cord-blood and those who received HLA-matched or HLA-mismatched donor blood. However, in patients with MRD-positive disease at the time of transplant, those who received a cord-blood transplant had significantly longer overall survival compared with those receiving an HLA-mismatched transplant. The risk of relapse was also significantly lower in the cord-blood group compared with both HLA-matched and HLA-unmatched transplants. • The probability of survival after receipt of a transplant from a cord-blood donor was comparable with that associated with other donors, and the risk of relapse was lower in the cord-blood group. Abstract

unrelated donor (344), or an HLA-mismatched unrelated donor (98). RESULTS The relative risks of death and relapse between the cord- blood group and the two other unrelated-donor groups appeared to vary according to the presence of minimal residual disease status before transplantation. Among patients with minimal residual disease, the risk of death was higher in the HLA-mismatched group than in the cord-blood group (hazard ratio, 2.92; 95% confidence interval [CI], 1.52 to 5.63; P=0.001); the risk was also higher in the HLA-matched group than in the cord-blood group but not significantly so (hazard ratio,

BACKGROUND The majority of patients in need of a hematopoietic-cell transplant do not have a matched related donor. Data are needed to inform the choice among various alternative donor-cell sources. METHODS In this retrospective analysis, we compared outcomes in 582 consecu- tive patients with acute leukemia or the myelodysplastic syndrome who received a first myeloablative hematopoietic-cell transplant from an unrelated cord-blood donor (140 patients), an HLA-matched

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY