Abstract
Acute biphenotypic leukemia or mixed phenotype acute leukemia (MPAL) is rare and considered high-risk. The optimal treatment and the role of allogeneic hematopoietic stem cell transplant (alloHCT) are unclear. Most prior case series include only modest numbers of transplanted patients. We analyzed the outcome of 95 carefully characterized alloHCT patients with MPAL reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2012. The median age was 20 years (range 1- 68). Among the 95 patients, 78 were in first complete remission (CR1) and 17 in CR2. Three-year overall survival (OS) 67% (95% confidence interval [CI] 57-76), leukemia-free survival (LFS) 56% (95% CI 46-66), relapse incidence 29% (95% CI 20-38) and non-relapse mortality 15% (95% CI 9-23) were encouraging. OS was best in younger patients (< 20), but no significant differences were observed between those 20-40 and > 40 years. A matched-pair analysis showed similar outcomes comparing MPAL cases to 375 acute myelogenous leukemia (AML) or 359 acute lymphoblastic leukemia (ALL) cases. MPAL patients had more acute and a non-significant increase of chronic graft-versus host disease (GVHD). No difference was observed between patients transplanted in CR1 versus CR2. AlloHCT is a promising treatment option for pediatric and adult patients with MPAL with encouraging long-term survival.
Introduction
Acute biphenotypic leukemias (ABiL) or mixed phenotype acute leukemias (MPAL) or hybrid acute leukemias are rare (0.6-5% of all acute leukemias) and were described many years ago. 1-5 MPAL are considered as “puzzling” due to their cell origin which may be a multipotent stem or progenitor cell. Originally, the European Group for the Immunologic Characterization of Leukemias (EGIL) established criteria for ABiL where points were assigned to specific markers of B lymphoid, T lymphoid and myeloid origin. 6 In 2008, the World Health Organization (WHO) revised the criteria for lineage assignment and introduced the term “mixed phenotype acute leukemia7”, but excluding those which could be classified under other cytogenetic or clinical categories. The optimal treatment approach to MPAL is unclear. In published case series that range in patient numbers between 13 and 117, allogeneic hematopoietic stem cell transplantation (alloHCT) was performed in 7 – 61 %. 1 However, not all cases were classified according to WHO and in most reports, transplant outcomes were not reported. In one expert review, chemotherapy according to acute lymphoblastic leukemia (ALL), followed by alloHSCT was the preferred approach 8, but definitive data are lacking. Generally, MPAL are considered high-risk with a poor prognosis, although younger patients may have a better outcome. In earlier series treated with chemotherapy, or in countries with limited resources, a longer-term survival of 15- 35% was described. 1,14 Therefore, we investigated the outcome of 95 well documented cases of MPAL receiving alloHCT reported to the CIBMTR. We describe their characteristics, overall survival (OS), leukemia-free survival (LFS) and treatment-related complications and compare these with AML or ALL.
Patients and Methods
The CIBMTR® is a combined research program between the National Marrow Donor Program®/Be The Match® and the Medical College of Wisconsin. It comprises a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on allogeneic and autologous HCT. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits and patients are followed longitudinally. Computerized checks for discrepancies, physicians' review of submitted data, and on site audits of participating centers ensure data quality. Studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. Protected Health Information used in the performance of such research is collected and maintained in CIBMTR's capacity as a Public Health Authority under the HIPAA Privacy Rule.
The CIBMTR collects data at two levels: Transplant Essential Data (TED) level and Comprehensive Report Form (CRF) level. The TED-level data is an internationally accepted standard data set that contains a limited number of key variables for all consecutive transplant recipients. TED-level data, with some additional details of donor and graft characteristics, comprise the obligatory data submitted to the SCTOD (Stem Cell Therapeutic Outcomes Database). When a transplant is registered with the CIBMTR, a subset of patients is selected for the CRF level of data collection through a weighted randomization scheme. The CRF-level captures additional patient, disease and treatment-related data. TED and CRF level data are collected pre-transplant, 100 days and six months post-transplant, annually until year 6 post-transplant and biannually thereafter until death.
Inclusion Criteria
We identified 261 cases that underwent allogeneic HCT for MPAL and reported to the CIBMTR since 1996. The immunophenotype reports of all cases were reviewed in detail (by RM) and 22 cases which did not meet the criteria of MPAL according to WHO 9 were excluded. Other excluded cases are 100 whose flow cytometry or biopsy reports could not be retrieved and 44 cases where the immunophenotype reports were received but incomplete. Ninety five cases with confirmed immunophenotypic criteria of MPAL were included in the analysis. Only 2 cases of the 95 selected qualified as bilineal.
End points
The primary endpoints were OS, leukemia-free survival (LFS), relapse incidence (REL), and non-relapse mortality (NRM). Secondary endpoints were engraftment, acute and chronic graft-versus host disease (GVHD). LFS was defined as survival with no evidence of relapse or progression. Relapse was defined as the reappearance of ≥ 5% blasts morphological evaluation in bone marrow or an extramedullary site. NRM was defined as death without evidence of relapse or progression. OS was defined as the time from alloHCT to death from any cause. Acute and chronic graft-versus-host disease (GVHD) were defined according to standard criteria 10.
Statistical analysis
Patient-, disease-, and transplant-related factors were summarized by presenting median and range for continuous variables and counts accompanied by percentages for categorical variables. Probabilities of overall survival and disease-free survival were calculated using the Kaplan-Meier estimator. The log-rank test was used to compare different groups of patients with respect to overall survival and disease-free survival. Cumulative incidences for GVHD, relapse, and treatment related mortality were calculated using the cumulative incidence function to account for competing risks. Gray's test was used to compare incidence of these outcomes between groups of patients.
In order to compare the outcomes of patients with MPAL to those with AML and ALL, a matched pairs study was carried out. MPAL patients (cases) were matched with controls diagnosed with AML and ALL.
For each MPAL case, 4 AML and 4 ALL controls satisfying the following criteria were selected: year of transplant +/- 3 years; age +/- 5 years; exact match for KPS, donor type, disease status (CR1/CR2). Two matched group analyses were performed separately.
AML analysis matching
96% were matched to 4 well matched controls. 1 had 3 well matched controls. 1 had 2 well matched controls. Two cases had 3 not well matched controls.
ALL analysis matching
90% of cases were matched to 4 well matched controls. 5 had 3 well matched controls. 3 had 2 well matched controls. 1 had 1 well matched control. 1 could not be matched and was deleted. 3 cases had 4 or less controls that were not well matched.
Variables that were adjusted for include
cytogenetics, WBC at diagnosis, extramedullary disease at diagnosis, Time from diagnosis to CR1, CR1 duration for patients in CR2, conditioning regimen, graft type, GVHD prophylaxis, and antithymocyte globulin (ATG)/alemtuzumab use. All of the outcomes were analyzed via marginal Cox model in order to account for dependence among matched individuals.
SAS 9.3 (SAS Inc., Cary, NC) statistical software was used for all analyses.
Results
Patient characteristics
Patient, disease and transplant characteristics are summarized in Table 1. During the study period (1996-2012), 95 patients with MPAL underwent alloHCT: 78 in first CR (CR1, 82%) and 17 in second CR (CR2, 18%). Fifty-two percent were male. Twenty-one percent had extramedullary disease at diagnosis. The median time from CR to alloHCT was 13 weeks for patients in CR1. For CR2 patients, the median duration of CR1 was 13 months. The most frequent phenotype of MPAL (58%) was myeloid with B cell markers (My+B) according to the WHO classification followed by My+T cell (33%, see also Fig. 1). Most had intermediate risk. Normal cytogenetics were found in 34% while other intermediate risk abnormalities by SWOG criteria were found in 19% and poor risk in 20%. The Bcr-Abl transcript or the Ph+ chromosome was found in 11% (all of these cases My+B phenotype). Forty-two HCT recipients had a related and 53 an unrelated donor (URD) including 29 cord blood (UCB); 18 single cords, 11 double cords. Bone marrow grafts were used in 37, peripheral blood stem cells (PBSC) in 33% and UCB in 31%. 81 (85%) received myeloablative conditioning. Only 3 received donor lymphocyte infusions (DLI) as treatment for post-transplant relapse.
Table 1. Patient Characteristics.
| N (%) | |
|---|---|
| Number of patients | 95 |
| Median age (range) | 20 years (1-68) |
| Disease status at transplant | |
| CR1 | 78 (82) |
| CR2 | 17 (18) |
| Time from CR1 to transplant for CR1 patients, median (range) | 13 weeks (2- 49) |
| Duration of CR1 for CR2, median (range) | 10 months (1-83) |
| Year of transplant | |
| 1996 – 2005 | 29 (31) |
| 2006 – 2008 | 40 (42) |
| 2009 – 2011 | 26 (27) |
| Recipient gender | |
| Male | 49 (52) |
| Female | 46 (48) |
| White blood cell count at diagnosis, median (range) | 17×104/mcL (1-617) |
| Extramedullary disease at diagnosis | |
| Yes (12 CNS, 8 other sites) | 20 (21) |
| No | 73 (77) |
| Missing | 2 (2) |
| Type of MPAL by WHO | |
| My+ B | 55 (58) |
| My+ T | 31 (33) |
| My+T+B | 6 (6) |
| B+T | 3 (3) |
| Cytogenetics/molecular type at diagnosis a | |
| Normal | 32 (34) |
| Poor risk | 19 (20) |
| Intermediate | 18 (19) |
| MLL + | 10 (11) |
| BCR/ABL + | 10 (11) |
| Missing | 5 (5) |
| Chemotherapy prior to transplant | |
| AML-type | 46 (48) |
| ALL-type | 16 (17) |
| Hybrid | 11 (12) |
| Missing | 22 (23) |
| Donor HLA matching | |
| Matched related | 33 (35) |
| Other related | 9 (9) |
| Unrelated, well matched | 7 (7) |
| Unrelated, partially matched | 3 (3) |
| Unrelated, mismatched | 3 (3) |
| Unrelated, matching unknown | 11 (12) |
| Umbilical cord blood | 29 (31) |
| Conditioning regimenb | |
| MA with TBI | 56 (59) |
| MA, no TBI | 25 (26) |
| RIC | 10 (11) |
| Missing | 4 (4) |
| Graft type | |
| Bone marrow | 35 (37) |
| Peripheral blood stem cells | 31 (33) |
| Umbilical cord blood | 29 (31) |
| Median follow-up of survivors (range) | 68 months (3- 167) |
cytogenetics criteria: favorable - per SWOG; trisomy 8 – trisomy 8 with or without 1 additional abnormality; MLL -MLL rearranged with different partners or 11q23 mentioned; intermediate - other intermediate per SWOG; BCR/ABL - t(9;22) or BCR/ABL documented, often with other abnormalities; poor - other poor per SWOG (including complex karyotypes)
type of induction therapy: AML - idarubicin, daunorubicin, doxorubicin, 7+3; ALL - Larson protocol, HyperCVAD, steroids, asparaginase
FIG. 1. Proportion of patients with the different immunophenotypes (My+ B= patients co-expressing myeloid and B lymphoid markers according to the WHO classification, My+ T= myeloid and T lymphoid markers, My+T+B= myeloid+ T+ B lymphoid, T+B= T+ B lymphoid.
Survival, LFS, relapse, NRM, and GVHD
The major outcomes are given in Table 2. At 3 years, OS was 67 % (95% confidence interval (CI) 57- 76); LFS 56% (95% CI 46- 66). A Kaplan-Meier plot for OS and LFS is shown in Fig. 2. At 3 years, the relapse incidence was 29% (95% CI 20- 38) and NRM was 15% (95% CI 9- 23). Acute GVHD grade II-IV at day 100 was 48% (95% CI 37- 58). Chronic GVHD at 3 years developed in 53% (95% CI 42- 63). In the group of 144 patients excluded because of missing phenotypes, OS, LFS and NRM were similar (data not shown). Both acute and chronic GVHD were lower in this group [33 (26-41)% versus 47 (36- 57)%, p 0.04 and 38 (30-47)% versus 52 (41-62)% at 3 years, p 0.05].
Table 2. Univariate analysis of outcomes.
| Outcomes | N Eval | Prob (95% CI) |
|---|---|---|
| aGVHD | 94 | |
| 100-day | 48 (37-58)% | |
| cGVHD | 95 | |
| 1-year | 44 (33-54)% | |
| 2-year | 53 (42-63)% | |
| 3-year | 53 (42-63)% | |
| Relapse | 94 | |
| 1-year | 17 (10-26)% | |
| 2-year | 25 (17-34)% | |
| 3-year | 29 (20-38)% | |
| Treatment related mortality | 94 | |
| 1-year | 14 (8-22)% | |
| 2-year | 15 (9-23)% | |
| 3-year | 15 (9-23)% | |
| Leukemia free survival | 94 | |
| 1-year | 69 (59-78)% | |
| 2-year | 60 (50-70)% | |
| 3-year | 56 (46-66)% | |
| Overall survival | 95 | |
| 1-year | 78 (69-85)% | |
| 2-year | 70 (60-79)% | |
| 3-year | 67 (57-76)% |
FIG. 2. Kaplan-Meier estimate of overall survival and leukemia-free survival of patients who underwent alloHCT for MPAL.
Prognostic factors for outcome
The outcomes in different categories of patients are shown in Table 3. No differences in OS were found in My+B versus My+T. Patients < 20 years had a trend to a longer survival, but survival was similar in those age 20-40 and older than 40 years. Survival was also similar in patients transplanted in CR1 vs. CR2. When the group with normal and intermediate cytogenetics was compared with the group of poor risk, MLL rearranged and Bcr-abl translocated cases, no statistically significant difference was found. Similarly, the white blood cell count at initial diagnosis, the serostatus of CMV and the year of transplant did not impact on the outcome of allotransplant (Table 3).
Table 3. Prognostic Factors.
| Factor | Categories | Survival at 2 years * | p-value (at 2 years) | p- value (overall) |
|---|---|---|---|---|
| Lineage | My+B (N = 55) | 67 (54-79)% | 0.53 | 0.22 |
| My+T (N = 31) | 74 (57-87)% | |||
| Age | < 20 (n=49) | 80 (67-90)% | 0.10 | 0.14 |
| 20-40 (N=24) | 61 (41-80)% | |||
| >40 (N=22) | 58 (37-78)% | |||
| Disease Status prior to HCT | CR1(N=78) | 70 (60-80)% | 0.99 | 0.88 |
| CR2 (N=17) | 70 (47-89)% | |||
| Cytogenetic Group | Normal/intermediate (N=51) | 68 (55-80)% | 0.56 | 0.78 |
| MLL/BCR-ABL/poor (N=39) | 74 (59-86)% | |||
| WBC at Diagnosis (107/L) | ≤ 20 (N=47) | 76 (63-87)% | 0.20 | 0.24 |
| >20 (N=42) | 64 (49-78)% | |||
| CMV Serostatus # | -/- (N=21) | 81 (62-94)% | 0.40 | 0.80 |
| -/+ (N=25) | 71(52-87)% | |||
| +/- (N=14) | 64(38-86)% | |||
| +/+ (N=28) | 60(42-77)% | |||
| Year of HCT | 1996- 2005 (N=29) | 72 (54-86)% | 0.58 | 0.49 |
| 2006- 2008 (N=40) | 65 (49-79)% | |||
| 2009- 2012 (N=26) | 76 (58-91)% |
Probability (95% Confidence Interval)
(-/- donor and recipient negative, -/+ donor negative, recipient positive, +/- donor positive, recipient negative for CMV IgG antibodies)
Matched pair analysis
The 95 cases of MPAL were matched with 375 patients with AML and 359 patients with ALL (Table 4). As shown in the Supplementary Table, OS, LFS and TRM were comparable between MPAL and those matched with AML or those matched with ALL. Unexpectedly, the MPAL cases had higher incidence of acute and a non-significant increase of chronic GVHD. This multivariate analysis (Table 5) comparing MPAL with AML and ALL essentially confirmed these outcomes.
Table 4. Univariate analysis matching AML versus ALL versus MPAL.
| AML (N = 375) | ALL (N = 359) | MPAL (N = 95) | ||
|---|---|---|---|---|
| Outcomes | N Eval Prob (95% CI) | N Eval Prob (95% CI) | N Eval Prob (95% CI) | p-value |
| aGVHD | 375 | 358 | 94 | PGray=0.01 |
| 100-day | 32 (27-37)% | 38 (33-43)% | 48 (37-58)% | 0.01 |
| cGVHD | 368 | 352 | 95 | PGray=0.02 |
| 1-year | 33 (28-38)% | 36 (31-41)% | 44 (33-54)% | 0.18 |
| 3-year | 36 (30-41)% | 42 (36-47)% | 53 (42-63)% | 0.02 |
| 5-year | 36 (30-41)% | 42 (36-47)% | 53 (42-63)% | 0.02 |
| Relapse | 375 | 358 | 94 | PGray=0.96 |
| 1-year | 22 (18-26)% | 23 (18-27)% | 17 (10-26)% | 0.50 |
| 3-year | 28 (24-33)% | 29 (20-38)% | 1.00 | |
| 5-year | 30 (25-34)% | 31 (26-36)% | 31 (22-41)% | 0.90 |
| Treatment related mortality | 375 | 358 | 94 | PGray=0.17 |
| 1-year | 16 (12-20)% | 18 (14-22)% | 14 (8-22)% | 0.60 |
| 3-year | 19 (15-23)% | 22 (18-27)% | 15 (9-23)% | 0.24 |
| 5-year | 20 (16-24)% | 23 (19-28)% | 15 (9-23)% | 0.16 |
| Leukemia free survival | 375 | 358 | 94 | PLogrank=0.25 |
| 1-year | 63 (58-67)% | 60 (54-65)% | 69 (59-78)% | 0.25 |
| 3-year | 53 (48-58)% | 49 (44-55)% | 56 (46-66)% | 0.42 |
| 5-year | 50 (45-56)% | 46 (40-51)% | 54 (44-64)% | 0.26 |
| Overall survival | 375 | 359 | 95 | PLogrank=0.37 |
| 1-year | 68 (63-73)% | 71 (66-75)% | 78 (69-85)% | 0.14 |
| 3-year | 57 (52-62)% | 57 (52-62)% | 67 (57-76)% | 0.18 |
| 5-year | 54 (49-59)% | 53 (47-58)% | 60 (50-70)% | 0.44 |
Table 5. Multivariate analysis of risk comparing MPAL with AML and MPAL with ALL.
| Outcomes (HR) | MPAL | AML | ALL |
|---|---|---|---|
| OS, HR (95% CI) | 1.00 | 0.76 (0.51- 1.14) | 0.79 (0.54- 1.14) |
| p-value | 0.20 | 0.21 | |
| DFS, HR (95% CI) | 1.00 | 1.21 (0.83- 1.78) | 1.27 (0.90- 1.79) |
| p-value | 0.32 | 0.17 | |
| TRM, HR (95% CI) | 1.00 | 1.25 (0.70- 2.24) | 1.55 (0.85- 2.84) |
| p-value | 0.45 | 0.16 | |
| Relapse, HR (95% CI) | 1.00 | 0.98 (0.60- 1.60) | 1.16 (0.78- 1.71) |
| p-value | 0.95 | 0.46 | |
| AGVHD, HR (95% CI) | 1.00 | 0.65 (0.45- 0.92) | 0.68 (0.49- 0.95) |
| p-value | 0.016 | 0.025 | |
| CGVHD, HR (95% CI) | 1.00 | 0.62 (0.46- 0.83) | 0.79 (0.57- 1.09) |
| p-value | 0.0031 | 0.14 |
Abbreviations: OS= overall survival, DFS= disease free survival, TRM= treatment related mortality, AGVHD= acute graft versus host disease, CGVHD= chronic graft versus host disease, HR: hazard ratio, if > 1, MPAL has a lower risk; if < 1, MPAL has a higher risk than the patient group to which it is compared. Hazard ratios with 95% confidence intervals are show
Discussion
This retrospective analysis of 95 well characterized patients from the CIBMTR describes a large series of patients with MPAL receiving alloHCT for this rare type of leukemia. Overall, the results show an encouraging outcome (OS 67% at 3 years, LFS 56% at 3 years) when compared with a SEER study. 1 Direct comparisons with population-based studies are difficult, because the indications for transplant and results of donor searches vary between centers and registries do not well characterize this leukemia subtype. The immunophenotype of our cases (58% B+M and 33% T+M) is similar to two reported non-transplant series. 4,11 The cytogenetic profile in the literature is more variable. 4,11-15 However, our cohort is younger selecting for those who were able to undergo alloHCT. Most Ph1+ cases with MPAL would now receive tyrosine-kinase inhibitors which might further improve their prognosis. 16 Based on the data we show here, alloHCT is a reasonable treatment option for the patient population with MPAL described here, despite the adverse impact of cytogenetics and high white cell count at diagnosis. Since the patients submitted to CIBMTR as MPAL but without complete phenotypes have similar outcomes, we are confident that our study represents MPAL in a younger population able to undergo alloHCT.
Only 3 prior studies focus exclusively on alloHCT for MPAL. In a pediatric study from Korea, 9 children with MPAL were reported 17 but alloHCT did not improve outcomes compared with their chemotherapy only group, mostly including high-risk infant leukemias. In a study from China, 59 patients with “leukemia of ambiguous lineage” 18 included young adult patients (median age 22-26 years) plus 6 cases of undifferentiated leukemia and 8 of “lineage switch” leukemia. The 5- year OS was 23.8±8.9% and 64.0 ± 8.4% (DFS 16.7 ±7.6% and 55.8 ±9.4%, respectively) in two patient groups. These divergent survival rates were attributed to two different (lower and higher intensity) conditioning regimens. In a study from Japan, 18 patients with MPAL who underwent alloHCT were reported.19 These patients were mostly adults; 5 of 18 patients > 50 years. The transplant results were favorable (5 year OS 71.8% for transplant in remission), but no patients survived if they were not in remission at the time of transplant. A matched pair analysis comparing their 18 cases of MPAL with 90 cases of AML and 90 cases of ALL showed similar OS, LFS or TRM at 5 years.
Our matched pair analysis showed outcomes comparable to either AML or ALL though MPAL experienced more frequent GVHD, yet a trend to lower TRM. The paradox of more GVHD with similar or improved OS is unexplained. It may be caused by other clinical covariates or better prevention of GVHD-related mortality not addressed in the matching algorithm. The smaller Japanese study also had a high incidence of acute and chronic GVHD. More research is necessary to clarify this issue.
Taken together, our observational study suggests that allogeneic transplant is a promising option for patients with MPAL in CR1 or CR2. Further characterization of the subgroups will determine which subgroups are served best by allografting.
Supplementary Material
Acknowledgments
CIBMTR Support List: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
*Corporate Members: The complete list of contributing centers can be found on the internet version of this manuscript.
Footnotes
Author Contributions: RM wrote the first draft of the manuscript; all authors approved the final version of the manuscript.
The authors do not have any conflict of interest to disclose.
Presented in part at the BMT Tandem Meeting, February 11- 15, 2015 in San Diego
Conflict of Interest: The authors declare no conflict of interest.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1.Shi R, Munker R. Survival of patients with mixed phenotype acute leukemias: A large population-based study. Leuk Res. 2015;39:606–616. doi: 10.1016/j.leukres.2015.03.012. [DOI] [PubMed] [Google Scholar]
- 2.Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia. 2010;24:1844–51. doi: 10.1038/leu.2010.202. [DOI] [PubMed] [Google Scholar]
- 3.Steensma DP. Oddballs: Acute leukemias of mixed phenotype and ambiguous origin. Hematol Oncol Clin N Am. 2011;25:1235–53. doi: 10.1016/j.hoc.2011.09.014. [DOI] [PubMed] [Google Scholar]
- 4.Yan L, Ping N, Zhu M, et al. Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification. Haematologica. 2012;97:1708–1712. doi: 10.3324/haematol.2012.064485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ben-Bassat I, Gale RP. Hybrid acute leukemias. Leuk Res. 1984;8:929–936. doi: 10.1016/0145-2126(84)90046-8. [DOI] [PubMed] [Google Scholar]
- 6.Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunologic characterization of acute leukemias. European Group for the Immunologic Characterization of Leukemias (EGIL) Leukemia. 1995;9:1783–6. [PubMed] [Google Scholar]
- 7.Borowitz MJ, Bene MC, Harris NL, et al. Acute leukaemias of ambiguous lineage. In: Swerdlow H, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th. Lyon (France): International Agency for Research on Cancer (IARC Press; 2008. pp. 150–155. [Google Scholar]
- 8.Wolach O, Stone RM. How I treat: mixed phenotype acute leukemia. Blood. 2015;125:123–131. doi: 10.1182/blood-2014-10-551465. [DOI] [PubMed] [Google Scholar]
- 9.Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008. [Google Scholar]
- 10.Flowers MED, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors of acute and chronic graft-versus host disease and for chronic graft versus host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–3219. doi: 10.1182/blood-2010-08-302109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Matutes E, Pickl WF, van't Veer M, et al. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood. 2011;117:3163–3171. doi: 10.1182/blood-2010-10-314682. [DOI] [PubMed] [Google Scholar]
- 12.Heesch S, Neumann M, Schwartz S, et al. Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization. Ann Hematol. 2013;92:747–758. doi: 10.1007/s00277-013-1694-4. [DOI] [PubMed] [Google Scholar]
- 13.Gerr H, Zimmermann M, Schrappe M, et al. Acute leukemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Brit J Haematol. 2010;149:84–92. doi: 10.1111/j.1365-2141.2009.08058.x. [DOI] [PubMed] [Google Scholar]
- 14.Deffis-Court M, Alvarado-Ibarra M, Ruiz-Argüelles, et al. Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in México. Ann Hematol. 2014;93:595–601. doi: 10.1007/s00277-013-1919-6. [DOI] [PubMed] [Google Scholar]
- 15.Manola KN. Cytogenetic abnormalities in acute leukemia of ambiguous lineage: an overview. Br J Haematol. 2013;163:24–39. doi: 10.1111/bjh.12484. [DOI] [PubMed] [Google Scholar]
- 16.Shimizu H, Yokohama A, Hatsumi N, et al. Philadelphia chromosome-positive mixed phenotype acute leukemia in the imatinib era. Eur J Haematol. 2014;93:297–301. doi: 10.1111/ejh.12343. [DOI] [PubMed] [Google Scholar]
- 17.Park JA, Ghim TT, Bae KW, et al. Stem cell transplant in the treatment of childhood biphenotypic acute leukemia. Pediatr Blood Cancer. 2009;53:444–452. doi: 10.1002/pbc.22105. [DOI] [PubMed] [Google Scholar]
- 18.Liu QF, Fan ZP, Wu MQ, et al. Allo-HSCT for acute leukemia of ambiguous lineage in adults: the comparison between standard conditioning and intensified conditioning regimens. Ann Hematol. 2013;92:679–687. doi: 10.1007/s00277-012-1662-4. [DOI] [PubMed] [Google Scholar]
- 19.Shimizu H, Saitoh T, Machida S, et al. Allogeneic hematopoietic stem cell transplantation for adult patients with mixed phenotype acute leukemia: results of a matched pair analysis. Eur J Haematol. 2015;93:297–301. doi: 10.1111/ejh.12516. [DOI] [PubMed] [Google Scholar]
- 20.Supplementary information accompanies this paper on the BBMT website (http://www.bbmt.org)
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.