Abstract
Autologous hematopoietic cell transplantation (autoHCT) is used for relapsed and recurrent malignant disorders and as part of initial therapy for selected malignancies. This study describes changes in utilization, techniques and survival in a population–based cohort including 68,404 patients who underwent first autoHCT in a US or Canadian center, 1994–2005, and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The highest annual mean autoHCTs performed (average 6,948 annually) occurred during 1996–1999, with a subsequent decrease (average 4,783 annually), mainly due to less autoHCTs for breast cancer. However, the annual mean of autoHCTs increased from 5,278 annually in 1994–1995 to 5,459 annually in 2004–2005, reflecting increased utilization for multiple myeloma (MM), non-Hodgkin (NHL) and Hodgkin lymphoma (HL). Despite an increase in the median age from 44 to 53 years, there has been a significant improvement in OS from 1994 to 2005 for patients with chemotherapy-sensitive relapsed NHL (Day +100 OS: 85 to 96%; 1 year OS: 68 to 80% P<0.001) and chemotherapy-sensitive MM (Day +100 OS: 96 to 98%; 1 year OS: 83 to 92% P<0.001). The OS improvement was most pronounced in middle aged (>40 years) and older (>60 years) individuals.
INTRODUCTION
Autologous hematopoietic cell transplant (autoHCT) is a curative modality for selected patients with hematologic malignancies, hematologic disorders and solid tumors. Over the past 20 years, the practice of autoHCT has evolved to include a new source of hematopoietic cells (peripheral blood),1 new diseases/indications for which autoHCT has demonstrated efficacy and improved survival,2–3 as well as elimination of utilization for some indications such as breast and ovarian cancer for which autoHCT has not been demonstrated to be superior to chemotherapy.4–6 Improvements in supportive care include anti-microbial agents, improved radiographic testing and the improvement in care that comes from increased experience with autoHCT utilization. Simultaneously, there have been major changes to cancer treatments with the development of monoclonal antibodies (rituximab, alemtuzumab), immunomodulatory drugs (thalidomide, lenalidomide), small molecule inhibitors (bortezomib, sirolimus, temsirolimus, everolimus), hypomethylating agents (azacitidine, decitabine) and other novel therapies. The introduction of these novel agents may have affected referral patterns and indications for autoHCT.7–9 In addition non-medical circumstances impact autoHCT applications, for example, variable insurance coverage for tandem autoHCT for myeloma.10–13
The existence of the Center for International Blood and Marrow Transplant Research (CIBMTR), a world-wide registry and observational database of HCT, makes it possible to study whether, and how, the utilization of HCT in the therapy of cancer and other disorders has changed over time, as well as evaluate historical trends in OS. The study reported herein describes the autoHCT patient population and analyzes OS in disease and age subgroups for the 12-year period, 1994 to 2005.
METHODS
About the CIBMTR
The CIBMTR was established in 2004 as a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR) and the National Marrow Donor Program (NMDP) which comprises a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive allogeneic and autologous hematopoietic cell transplantations to a Statistical Center at the Medical College of Wisconsin in Milwaukee and the NMDP Coordinating Center in Minneapolis. The IBMTR has been collecting allogeneic HCT data from centers worldwide since 1972 and the ABMTR has collected autologous HCT data from centers in North and South America since 1991. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally. Computerized checks for discrepancies, physicians’ review of submitted data and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed under guidance of the Institutional Review Boards of the Medical College of Wisconsin and the NMDP and are in compliance with all applicable federal regulations pertaining to the protection of human research participants.
Data Collection and Reporting
The CIBMTR collects data at two levels: Transplant Essential Data (TED) and Comprehensive Report Form (CRF) data. TED data include disease type, age, sex, pretransplant disease stage and chemotherapy-responsiveness, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, post-transplant disease progression and survival, development of a new malignancy and cause of death. All CIBMTR teams contribute TED data. More detailed disease and pre- and post-transplant clinical information are collected on a subset of registered patients selected for CRF data by a weighted randomization scheme. TED and CRF level data are collected pre-transplant, 100 days and 6 months post-transplant and annually thereafter until death. The causes of death whether due to disease, treatment-related mortality or other cause were not available for all patients (only the subset of registered patients), thus overall survival, and not cause-specific deaths, are reported.
Study Population
To obtain the broadest representation of HCT utilization for this study, TED-level CIBMTR data were used. The study selection criteria were first autologous HCT at US or Canada centers performed between 1994 and 2005. The final study population consisted of 68,404 first autologous HCTs.
Two hundred six unique transplant centers contributed data to the CIBMTR during the study period. Eighty centers (39%) reported at least one autoHCT to the CIBMTR during each of the 12 years in the study period (1994–2005, inclusive). Fifty-one (25%) provided data for less than half of the study period.
Statistical Analysis
Six cohorts, each consisting of 2-year time periods, were determined to be the best delineation of the study period to describe trends over time. Descriptive statistics, including proportions, median and ranges were calculated. There were no tests of statistical significance for volume data. Overall survival (OS) estimates and 95% confidence intervals were calculated at Day +100, which represents early transplant-related mortality (TRM), and at one year, which represents disease-related mortality and later TRM. Statistical significance was measured using Ptrend over the 6 time cohorts to test whether the OS estimates were stable (slope = 0), increasing (slope>0) or decreasing (slope<0) over time. OS estimates were determined for a priori defined disease and disease status subgroups and are not adjusted for any covariates such as age, KPS, etc. Disease status subgroups with significant trends in OS over time were stratified by age to determine the pattern of OS trends by age. To reduce the type I error, P<0.01 was considered statistically significant.
Estimation of the rate of AutoHCT over time
The age-specific incidence of 6 major hematologic disorders (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], Hodgkin lymphoma [HL], non-Hodgkin lymphoma [NHL], multiple myeloma [MM], and myelodysplastic syndromes [MDS]) was obtained from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) database from 1994 to 2005 (http://seer.cancer.gov/). The age-specific intercensal population estimates from 1994 to 2005 were obtained from the U.S. Census Bureau (http://www.census.gov). The number of new cases of each disease by age group and year was estimated by applying the age-specific SEER incidence to the U.S. national population in that age group. AutoHCTs for these 6 major hematologic disorders were actual numbers reported to the CIBMTR that captured approximately 45–70% of all autoHCTs performed at a U.S. transplant center during the period 1994–2005. Therefore, an inflation factor of 1.33 – 1.54 was applied to account for variances in the proportion of all autoHCTs performed in the US that were reported to the CIBMTR. The rate of patients who received an autoHCT for each disease was calculated by dividing the number of autoHCTs (after applying the inflation factor) by the number of newly diagnosed cases, excluding incident cases and autoHCTs for persons ≥75 years and excluding autoHCTs performed in Canada.
RESULTS
Patient Characteristics
Characteristics of patients who received an autoHCT are summarized in Table 1. The 4 years from 1996–1999 had the highest number of autoHCTs performed (N=27,794), with a decrease in volume in the subsequent 4 year period (N=19,135 in the years 2000–2003). The number of transplant centers with active reporting in any 2-year period ranged from 197 to 241. The median age increased by almost a decade over the study period (44 years in 1994–1995 to 53 years in 2004–2005). While the number of autoHCT recipients aged 70 years or older has increased, they compose only 5% of all autoHCTs performed. In comparison, 60-year olds constitute 25%, and 50-year olds constitute an additional 30% of all autoHCT recipients. Since the year 2000, half of all autoHCTs have been performed for older (≥50 years) adults. Collection of Karnofsky performance score (KPS) has improved over the entire study period with 60% missing data in the 1994–1995 period and 15% missing data in the 2004–5 group. Due to incomplete data on KPS for most of the study period, it is difficult to assess changes in this patient characteristic over time. Between 1997 and 1998 there was an improvement in completeness of data collected for race. Since 1998, the proportion of autoHCTs for non-White race/ethnicities has remained stable. The number of autoHCTs performed in Canada increased by >60% between 1994–1995 and 2004–2005.
Table 1.
Characteristics of patients from the U.S. and Canada who received and registered an autologous transplant to the CIBMTR, 1994–2005.
| Variable | 1994–1995 N (%) |
1996–1997 N (%) |
1998–1999 N (%) |
2000–2001 N (%) |
2002–2003 N (%) |
2004–2005 N (%) |
|---|---|---|---|---|---|---|
| Patient related | ||||||
| Number of patients | 10,557 | 13,665 | 14,129 | 9686 | 9449 | 10,918 |
| Number of centers | 197 | 225 | 241 | 229 | 210 | 203 |
| Age | ||||||
| Median (range), years | 44 (<1–75) | 46 (<1–76) | 48 (<1–78) | 50 (<1–78) | 52 (<1–91) | 53 (<1–81) |
| < 1–9 | 435 ( 4) | 430 ( 3) | 577 ( 4) | 434 ( 4) | 503 ( 5) | 532 ( 5) |
| 10–19 | 384 ( 4) | 386 ( 3) | 419 ( 3) | 342 ( 4) | 305 ( 3) | 366 ( 3) |
| 20–29 | 819 ( 8) | 849 ( 6) | 838 ( 6) | 708 ( 7) | 599 ( 6) | 680 ( 6) |
| 30–39 | 2129 (20) | 2363 (17) | 2060 (15) | 1121 (12) | 902 (10) | 907 ( 8) |
| 40–49 | 3453 (33) | 4406 (32) | 3945 (28) | 2004 (21) | 1689 (18) | 1824 (17) |
| 50–59 | 2622 (25) | 3845 (28) | 4438 (31) | 2960 (31) | 2869 (30) | 3292 (30) |
| 60–69 | 671 ( 6) | 1317 (10) | 1731 (12) | 1902 (20) | 2203 (23) | 2766 (25) |
| ≥ 70 | 22 (<1) | 54 (<1) | 111 ( 1) | 203 ( 2) | 377 ( 4) | 548 ( 5) |
| Missing | 22 (<1) | 15 (<1) | 10 (<1) | 12 (<1) | 2 (<1) | 3 (<1) |
| Male gender | 3549 (34) | 4352 (32) | 4995 (35) | 5306 (55) | 5382 (57) | 6463 (59) |
| Missing | 58 ( 1) | 11 (<1) | 56 (<1) | 12 (<1) | 26 (<1) | 25 (<1) |
| Karnofsky/Lansky performance score | ||||||
| ≥ 80 | 4012 (38) | 5171 (38) | 4659 (33) | 6426 (66) | 7293 (77) | 8631 (79) |
| < 80 | 231 ( 2) | 302 ( 2) | 291 ( 2) | 427 ( 4) | 479 ( 5) | 617 ( 6) |
| Missing | 6314 (60) | 8192 (60) | 9179 (65) | 2833 (29) | 1677 (18) | 1670 (15) |
| Race | ||||||
| White | 6297 (60) | 8910 (65) | 11,402 (81) | 7731 (80) | 7455 (79) | 8653 (79) |
| African-American | 458 (4) | 661 ( 5) | 1056 (7) | 830 (9) | 912 (10) | 1063 (10) |
| Asian/Pacific Islander | 110 (1) | 159 ( 1) | 225 (2) | 181 (2) | 150 ( 2) | 186 ( 2) |
| Hispanic | 259 (2) | 332 ( 2) | 538 (4) | 330 (3) | 281 ( 3) | 228 ( 2) |
| Other | 34 (<1) | 46 (<1) | 80 (1) | 116 (1) | 158 ( 2) | 426 ( 4) |
| Missing | 3399 (32) | 3557 (26) | 828 (6) | 498 (5) | 493 ( 5) | 362 ( 3) |
| Country | ||||||
| US | 9820 (93) | 12674 (93) | 12998 (92) | 8560 (88) | 8323 (88) | 9717 (89) |
| Canada | 737 (7) | 991 ( 7) | 1131 (8) | 1126 (12) | 1126 (12) | 1201 (11) |
| Disease related | ||||||
| Disease | ||||||
| Multiple myeloma | 678 (6) | 1360 (10) | 2317 (16) | 3091 (32) | 3858 (41) | 4773 (44) |
| Non-Hodgkin lymphoma | 2573 (24) | 3060 (22) | 3079 (22) | 3140 (32) | 2842 (30) | 3164 (29) |
| Hodgkin lymphoma | 906 (9) | 1007 ( 7) | 1158 (8) | 1098 (11) | 1135 (12) | 1302 (12) |
| Solid tumor (not breast cancer) | 968 (9) | 1263 ( 9) | 1445 (10) | 883 (9) | 892 ( 9) | 963 ( 9) |
| Acute myeloid leukemia (AML) | 639 (6) | 499 ( 4) | 575 (4) | 442 (5) | 472 ( 5) | 506 ( 5) |
| Breast cancer | 4401 (42) | 6148 (45) | 5199 (37) | 815 (8) | 125 ( 1) | 61 ( 1) |
| Acute lymphoblastic leukemia (ALL) | 133 (1) | 79 ( 1) | 75 (1) | 40 (<1) | 27 (<1) | 43 (<1) |
| Chronic lymphocytic leukemia (CLL) | 28 (<1) | 47 (<1) | 80 (1) | 61 (1) | 27 (<1) | 24 (<1) |
| Autoimmune diseases | 0 | 12 (<1) | 36 (<1) | 49 (1) | 28 (<1) | 22 (<1) |
| Myelodysplastic syndrome/Myeloproliferative disorder (MDS/MPS) | 22 (<1) | 22 (<1) | 33 (<1) | 24 (<1) | 16 (<1) | 13 (<1) |
| Other leukemia | 63 (1) | 52 (<1) | 27 (<1) | 15 (<1) | 12 (<1) | 11 (<1) |
| Chronic myeloid leukemia (CML) | 88 (1) | 67 (<1) | 80 (1) | 17 (<1) | 4 (<1) | 5 (<1) |
| Other | 42 (<1) | 32 (<1) | 18 (<1) | 9 (<1) | 11 (11) | 31 (<1) |
| Missing | 16 (<1) | 17 (<1) | 7 (<1) | 2 (<1) | 0 | 0 |
| Disease status pre-transplant | ||||||
| AML | ||||||
| 1st complete remission (CR) | 336 (53) | 262 (53) | 313 (54) | 276 (62) | 329 (70) | 338 (67) |
| 2nd or greater CR | 148 (23) | 108 (22) | 139 (24) | 95 (21) | 100 (21) | 126 (25) |
| Relapse/Primary induction failure | 91 (14) | 63 (13) | 68 (12) | 31 ( 7) | 23 ( 5) | 22 ( 4) |
| Other/Unknown/Missing | 64 (10) | 66 (13) | 55 (10) | 40 ( 9) | 20 ( 4) | 20 ( 4) |
| ALL | ||||||
| 1st CR | 46 (35) | 30 (38) | 29 (39) | 23 (58) | 18 (67) | 28 (65) |
| 2nd or greater CR | 63 (47) | 28 (35) | 23 (31) | 10 (25) | 7 (26) | 10 (23) |
| Relapse/Primary induction failure | 17 (13) | 12 (15) | 14 (19) | 6 (15) | 1 ( 4) | 1 ( 3) |
| Other/Unknown/Missing | 7 ( 5) | 9 (11) | 9 (12) | 1 ( 3) | 1 ( 4) | 4 ( 9) |
| Non-Hodgkin lymphoma | ||||||
| 2nd CR /1st chemosensitive relapse | 895 (35) | 1073 (35) | 1050 (34) | 1026 (33) | 952 (34) | 1118 (35) |
| 1st CR | 238 ( 9) | 241 ( 8) | 363 (12) | 409 (13) | 509 (18) | 636 (20) |
| ≥3rd CR / ≥2nd chemosensitive relapse | 211 ( 8) | 252 ( 8) | 304 (10) | 274 ( 9) | 226 ( 8) | 259 ( 8) |
| Other/Unknown/Missing | 1229 (48) | 1494 (49) | 1362 (44) | 1431 (46) | 1155 (41) | 1151 (36) |
| Hodgkin lymphoma | ||||||
| 2nd CR /1st chemosensitive relapse | 348 (38) | 387 (38) | 468 (41) | 440 (40) | 477 (42) | 578 (44) |
| 1st CR | 21 ( 2) | 21 ( 2) | 47 ( 4) | 50 ( 5) | 47 ( 4) | 81 ( 6) |
| ≥3rd CR / ≥2nd chemosensitive relapse | 106 (12) | 88 ( 9) | 113 (10) | 94 ( 9) | 70 ( 6) | 100 ( 8) |
| Other/Unknown/Missing | 431 (48) | 511 (51) | 530 (46) | 514 (47) | 541 (48) | 543 (42) |
| Multiple Myeloma | ||||||
| 1st complete or partial remission | 153 (23) | 366 (27) | 667 (29) | 1554 (50) | 2407 (62) | 3196 (67) |
| Othera | 342 (50) | 499 (37) | 648 (28) | 802 (26) | 907 (24) | 1009 (21) |
| Unknown/Missing | 183 (27) | 495 (36) | 1002 (43) | 735 (24) | 544 (14) | 568 (12) |
| Transplant related | ||||||
| Time from diagnosis to transplant | ||||||
| Median (range) | 14 (<1–563) | 12 (<1–619) | 11 (<1–850) | 11 (<1–734) | 10 (<1–411) | 10 (<1–877) |
| < 12 months | 4472 (42) | 6414 (47) | 7049 (50) | 4899 (51) | 5133 (54) | 6035 (55) |
| 12–23 months | 2068 (20) | 2391 (17) | 2566 (18) | 2024 (21) | 1886 (20) | 2271 (21) |
| 24–35 months | 1105 (10) | 1325 (10) | 1262 (9) | 891 (9) | 731 (8) | 883 (8) |
| ≥ 36 months | 2351 (22) | 2842 (21) | 2658 (19) | 1497 (15) | 1379 (15) | 1656 (15) |
| Missing | 561 ( 5) | 693 ( 5) | 594 (4) | 375 (4) | 320 (3) | 73 (1) |
| Graft sourceb | ||||||
| Peripheral blood | 6288 (60) | 11253 (82) | 12961 (92) | 9104 (94) | 9104 (96) | 10618 (97) |
| Bone marrow | 2730 (26) | 1470 (11) | 657 (5) | 296 (3) | 193 (2) | 208 (2) |
| Bone marrow and peripheral blood | 1539 (15) | 942 ( 7) | 509 (4) | 286 (3) | 151 (2) | 92 (1) |
| High dose therapy regimens | ||||||
| Melphalan | 205 (2) | 486 (4) | 1089 (8) | 1989 (21) | 2833 (30) | 3828 (35) |
| BEAM | 73 (1) | 141 (1) | 537 (4) | 805 (8) | 1066 (11) | 1222 (11) |
| Cy+Etoposide+Nitrosourea | 1219 (12) | 1469 (11) | 1474 (10) | 1100 (11) | 826 (9) | 944 (9) |
| Bu+Cy ± other | 1173 (11) | 1162 (9) | 1128 (8) | 938 (10) | 800 (8) | 730 (7) |
| Cy ± other | 2471 (23) | 2900 (21) | 2356 (17) | 847 (9) | 485 (5) | 404 (4) |
| Cy+TBI ± other | 1135 (11) | 1021 (7) | 1015 (7) | 647 (7) | 370 (4) | 321 (3) |
| Etoposide + Melphalan ± other | 165 (2) | 142 (1) | 154 (1) | 99 (1) | 116 (1) | 260 (2) |
| BEAM+MAB ± other | 0 | 0 | 14 (<1) | 43 (<1) | 100 (1) | 200 (2) |
| Bu+Etoposide ± other | 67 (1) | 69 (1) | 142 (1) | 94 (1) | 137 (1) | 147 (1) |
| Carboplatin + Etoposide + Melphalan ± other | 104 (1) | 166 (1) | 240 (2) | 95 (1) | 204 (2) | 134 (1) |
| Carboplatin + Thiotepa ± other | 146 (1) | 147 (1) | 146 (1) | 116 (1) | 147 (2) | 94 ( 1) |
| Melphalan ± other (no radiation) | 34 (<1) | 41 (<1) | 193 (1) | 151 (2) | 102 (1) | 89 ( 1) |
| Carboplatin + Etoposide | 66 (1) | 97 (1) | 58 (<1) | 53 (1) | 69 (1) | 88 ( 1) |
| TBI ± other | 234 (2) | 540 (4) | 732 (5) | 357 (4) | 78 (1) | 78 ( 1) |
| Bu+ Melphalan ± other (no Thio) | 36 (<1) | 65 (<1) | 46 (<1) | 34 (<1) | 42 (<1) | 72 ( 1) |
| Bu+ Melphalan +Thiotepa ± other | 41 (<1) | 165 (1) | 141 (1) | 58 (1) | 28 (<1) | 70 ( 1) |
| Cy+Thiotepa+Carboplatin | 1625 (15) | 2793 (20) | 2854 (20) | 380 (4) | 33 (<1) | 21 (<1) |
| Carboplatin + Etoposide + Ifosfamide ± other | 164 (2) | 109 (1) | 77 (1) | 27 (<1) | 18 (<1) | 5 (<1) |
| Other | 1304 (12) | 1374 (10) | 1120 (8) | 457 (5) | 374 (4) | 399 ( 4) |
| Missing | 295 (3) | 778 (6) | 613 (4) | 1396 (14) | 1621 (17) | 1812 (17) |
| Type of 2nd transplant | ||||||
| 1 transplant only | 9741 (92) | 12609 (92) | 12980 (92) | 8636 (89) | 8230 (87) | 9151 (84) |
| 2 or more transplants | ||||||
| 1st autologous-2nd allogeneic, 2nd planned | 1 (<1) | 4 (<1) | 7 (<1) | 24 (<1) | 61 (1) | 145 (1) |
| 1st autologous-2nd allogeneic, 2nd not planned | 193 (2) | 282 (2) | 380 (3) | 429 (4) | 505 (5) | 485 (4) |
| 1st autologous-2nd autologous, 2nd planned | 167 (2) | 289 (2) | 313 (2) | 277 (3) | 285 (3) | 786 (7) |
| 1st autologous-2nd autologous, 2nd not planned | 455 (4) | 479 (4) | 447 (3) | 317 (3) | 364 (4) | 345 (3) |
| Missing | 0 | 2 (<1) | 2 (<1) | 3 (<1) | 4 (<1) | 6 (<1) |
Abbreviations: Cy=Cyclophosphamide; TBI=Total Body Irradiation; Bu=Busulfan; BEAM=Nitrosourea+Etoposide+ARAC+Melphalan; MAB=Monoclonal antibody.
Others include: Minimal Response, No Response/Stable Disease, Progression/Relapse, 2nd or greater Complete Remission
There was one autologous cord blood transplant between 2002–2003 in a 1 year old with severe aplastic anemia.
Disease Indications and High-dose Regimens
While the majority of autoHCTs performed in 1994–1995 were for breast cancer (42%) and NHL (24%), the most recent cohort in 2004–2005 demonstrates that multiple myeloma (MM, 44%), NHL (29%) and HL (12%) were the most common diseases for which autoHCT was performed. The peak of autoHCT for breast cancer was 1996–1997 (yearly average N=3,074) and by 2004–2005, the yearly average was 61. In contrast, 678 autoHCTs (yearly average N=339) were performed for MM in 1994–1995 compared to a peak of 4,773 (yearly average N=2,386) in the most recent cohort. In 1994–1995, the majority of MM autoHCTs 1994–1995 were performed for patients with advanced disease rather than for patients in first complete or partial remission (50% vs. 23%, respectively) whereas the opposite was observed in the 2004–2005 cohort (21% vs. 67%, respectively). Similarly, autoHCT was used to treat patients with early stage disease in acute leukemia (AML, ALL), and Hodgkin lymphoma (HL), more frequently with an increase in the proportion of patients transplanted within 12 months after diagnosis (42% in 1994–1995, 55% in 2004–2005).
The high -dose therapy regimens used for autoHCT have changed over time, in parallel to the changes in diseases treated. Cyclophosphamide+Thiotepa+Carboplatin, commonly used to treat breast cancer, declined from a peak of 1,427 annually in 1998–1999 to a low of 10 annually in 2004–2005. Melphalan, used for treatment of MM, increased from a low of 103 annually in 1994–1995 to a high of 1,914 annually in 2004–2005. Carmustine+etoposide+cytosine arabinoside+ melphalan (BEAM), commonly used to treat lymphoma, has increased from 37 annually in 1994–1995 to 611 annually in 2004–2005. Cy+TBI use decreased reflecting the decreased use of the regimen for NHL patients. “Other” regimens have declined from 652 annually in the earliest cohort to 200 annually in the latest cohort, suggesting that the use of “standard” regimens has increased.
The use of planned tandem autoHCTs has increased from 167 in 1994–1995 to 786 in 2004–2005, most likely reflecting the increase in autoHCT for MM. The frequency of a second unplanned autoHCT remained stable over the study period. The numbers of planned and unplanned second allogeneic HCT after a first autoHCT have both increased over time to 145 and 485, respectively in the most recent cohort.
Utilization of AutoHCT Over Time
The rate of autoHCT over time is summarized in Table 2. The U.S. population aged 0–74 years increased by 10.6% between 1994 and 2005. For NHL, the incident rate remained stable, and the incident cases increased by 10.3% which corresponds to the increase in the U.S. population. The rate of autoHCT for NHL initially increased by 20% (from 3.2 to 3.8%) between the 1994–1995 and 1996–1997 cohorts, then decreased in the 2002–2003 and 2004–2005 cohorts close to the baseline rate in 1994–1995. For HL, the incident rate increased by 4%, and the incident cases increased by 15% which exceeds the increase in the U.S. population, and the rate of autoHCT for HL increased by 28% during this time from 6.1% to 7.8%. For MM, the incident rate increased by 8%, and the incident cases increased by 20% which exceeds the rate of increase in the U.S. population; however, the rate of autoHCT for MM increased by almost 5-fold during this time from 5.1% to 25.1%. For AML, the incident rate in 0–74 year olds decreased by 10%, while the incident cases increased by 2%, and the rate of autoHCT for AML decreased by 12% over this time from 4.3% to 3.8%. For ALL, the incident rate in 0–74 year olds increased by 14%, and the incident cases increased by 18%; however, the rate of autoHCT for ALL decreased by 71% to 0.5%.
Table 2.
Changes over time in the U.S population, incident cases and proportion of cases who received an autologous HCT
| Calendar Year | 1994–1995 | 1996–1997 | 1998–1999 | 2000–2001 | 2002–2003 | 2004–2005 | |
|---|---|---|---|---|---|---|---|
| Total U.S population aged 0–74 years, in millions | 249.9 | 255.5 | 261.2 | 266.8 | 271.6 | 276.5 | |
| Acute Myeloid Leukemia (AML) | Incidence rate per 100,000 persons | 5.2 | 5.0 | 5.2 | 5.5 | 5.0 | 4.7 |
| Number of new incident cases aged 0–74 years | 12,879 | 12,683 | 13,682 | 14,608 | 13,532 | 13,131 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | 6.6% | 5.3% | 5.5% | 3.9% | 4.8% | 5.0% | |
| Acute Lymphoblastic Leukemia (ALL) | Incidence rate per 100,000 persons | 2.9 | 3.0 | 3.0 | 3.0 | 3.1 | 3.3 |
| Number of new incident cases aged 0–74 years | 7,706 | 7,592 | 7,926 | 8,055 | 8,404 | 9,067 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | 2.6% | 1.5% | 1.3% | 0.7% | 0.4% | 0.6% | |
| Myelodysplastic syndrome/ Myeloproliferative disorder (MDS/MPS) | Incidence rate per 100,000 persons | * | * | * | * | 3.8 | 3.9 |
| Number of new incident cases aged 0–74 years | * | * | * | * | 10,226 | 10,764 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | * | * | * | * | 0.2% | 0.2% | |
| Non-Hodgkin lymphoma (NHL) | Incidence rate per 100,000 persons | 29.5 | 28.4 | 27.9 | 28.0 | 28.7 | 29.4 |
| Number of new incident cases aged 0–74 years | 73,658 | 72,650 | 72,925 | 74,614 | 77,973 | 81,272 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | 4.9% | 5.9% | 5.6% | 5.3% | 4.6% | 4.5% | |
| Hodgkin Lymphoma (HL) | Incidence rate per 100,000 persons | 5.1 | 5.2 | 5.3 | 5.1 | 5.2 | 5.3 |
| Number of new incident cases aged 0–74 years | 12,787 | 13,330 | 13,856 | 13,707 | 14,212 | 14,706 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | 9.4% | 10.0% | 10.8% | 10.1% | 10.0% | 10.3% | |
| Multiple Myeloma (MM) | Incidence rate per 100,000 persons | 7.4 | 7.4 | 7.5 | 7.7 | 7.7 | 8.0 |
| Number of new incident cases aged 0–74 years | 18,422 | 19,006 | 19,498 | 20,468 | 20,863 | 22,123 | |
| Rate of AutoHCTs aged 0–74 years per New Incident cases | 5.1% | 9.8% | 15.6% | 18.3% | 22.6% | 25.1% | |
SEER did not initiate data collection for MDS/MPD until 2001.
Overall Survival
OS estimates at 100 days after autoHCT were, in general, high for all diseases examined and improved significantly over time for NHL in second complete remission (CR2) or first chemotherapy-sensitive relapse (1st sensitive relapse) and myeloma in first complete or partial remission (CR1/PR1) especially in patients above the age of 40 years (Table 3). Statistically significant improvements in 1-year OS after autoHCT were observed for NHL in CR2 or 1st sensitive relapse, and myeloma in CR1/PR1 at the time of HCT. Although the 1-year OS has improved over time there is a significant decline in OS between the Day 100 and 1-year time points, especially for patients with NHL in CR2/Rel1sen and chemotherapy-resistant lymphoma and myeloma, likely reflecting relapse of the underlying malignancy suggesting a need for improved disease control in these patients.
Table 3.
Overall Survival estimates by disease and disease status subgroups, stratified by age at autoHCT
| Disease/Disease Status at HCT | 1994–1995 | 1996–1997 | 1998–1999 | 2000–2001 | 2002–2003 | 2004–2005 | Ptrend |
|---|---|---|---|---|---|---|---|
| NHL in 2nd Complete Remission or 1st Chemotherapy-sensitive Relapse | All patients | ||||||
| Number of patients | 890 | 1067 | 1041 | 1020 | 946 | 1116 | |
| OS (95% CI) at 100 days post-HCT | 89 (87–91) | 90 (88–92) | 90 (88–92) | 94 (92–95) | 94 (92–95) | 95 (94–97) | <0.001 |
| OS (95% CI) at 1 year post-HCT | 68 (65–71) | 69 (66–72) | 72 (69–75) | 77 (75–80) | 78 (75–80) | 80 (77–83) | <0.001 |
| Subgroup analysis Age 20–39 yrs at time of HCT * | |||||||
| Number of patients | 177 | 159 | 152 | 132 | 87 | 111 | |
| OS (95% CI) at 100 days post-HCT | 96 (93–98) | 91 (86–95) | 97 (93–99) | 96 (92–99) | 94 (88–98) | 97 (93–99) | 0.3116 |
| OS (95% CI) at 1 year post-HCT | 76 (70–82) | 67 (59–74) | 81 (74–87) | 82 (75–89) | 82 (73–90) | 80 (71–88) | 0.0365 |
| Subgroup analysis Age 40–59 yrs at time of HCT | |||||||
| Number of patients | 551 | 640 | 622 | 572 | 516 | 585 | |
| OS (95% CI) at 100 days post-HCT | 88 (85–91) | 91 (89–93) | 90 (87–92) | 94 (92–96) | 95 (93–97) | 95 (93–96) | <0.001 |
| OS (95% CI) at 1 year post-HCT | 68 (64–72) | 74 (70–77) | 75 (71–78) | 81 (77–84) | 82 (78–85) | 80 (76–84) | <0.001 |
| Subgroup analysis Age ≥ 60 yrs at time of HCT | |||||||
| Number of patients | 133 | 233 | 237 | 294 | 316 | 400 | |
| OS (95% CI) at 100 days post-HCT | 85 (78–91) | 86 (81–90) | 86 (81–90) | 91 (88–94) | 93 (90–96) | 96 (93–97) | <0.001 |
| OS (95% CI) at 1 year post-HCT | 58 (49–66) | 57 (51–64) | 60 (53–67) | 69 (63–74) | 71 (65–76) | 79 (75–83) | <0.001 |
|
| |||||||
| NHL with No Prior Complete Remission (Induction Failure) | All patients | ||||||
| Number of patients | 522 | 564 | 587 | 691 | 390 | 318 | |
| OS (95% CI) at 100 days post-HCT | 86 (82–88) | 88 (85–90) | 87 (84–89) | 89 (86–91) | 88 (84–91) | 90 (87–93) | 0.2810 |
| OS (95% CI) at 1 year post-HCT | 67 (63–71) | 67 (63–71) | 71 (67–74) | 70 (66–73) | 68 (63–73) | 68 (62–73) | 0.7946 |
|
| |||||||
| HL in 2nd Complete Remission or 1st Chemotherapy-sensitive Relapse | All patients | ||||||
| Number of patients | 348 | 384 | 466 | 435 | 477 | 573 | |
| OS (95% CI) at 100 days post-HCT | 95 (92–97) | 95 (92–97) | 96 (94–97) | 97(95–98) | 96 (94–98) | 97 (95–98) | 0.4758 |
| OS (95% CI) at 1 year post-HCT | 86 (82–89) | 87 (84–91) | 87 (83–90) | 89 (85–92) | 90 (87–93) | 91 (88–93) | 0.1985 |
|
| |||||||
| HL with No Prior Complete Remission (Induction Failure) | All patients | ||||||
| Number of patients | 125 | 144 | 185 | 214 | 180 | 186 | |
| OS (95% CI) at 100 days post-HCT | 90 (85–95) | 89 (84–94) | 87 (82–92) | 92 (88–95) | 95 (92–98) | 93 (89–96) | 0.0667 |
| OS (95% CI) at 1 year post-HCT | 76 (68–83) | 73 (66–81) | 69 (62–76) | 77 (71–83) | 78 (71–84) | 79 (72–85) | 0.3786 |
|
| |||||||
| MM in 1st Complete or Partial Remission | All patients | ||||||
| Number of patients | 276 | 541 | 718 | 1567 | 2423 | 3192 | |
| OS (95% CI) at 100 days post-HCT | 96 (94–98) | 96 (94–98) | 96 (94–97) | 97 (96–98) | 98 (97–98) | 98 (98–99) | <0.001 |
| OS (95% CI) at 1 year post-HCT | 83 (79–88) | 84 (81–87) | 87 (85–90) | 90 (89–92) | 92 (91–93) | 92 (91–93) | <0.001 |
| Subgroup analysis Age 20–39 yrs at time of HCT | |||||||
| Number of patients | 19 | 30 | 32 | 74 | 76 | 105 | |
| OS (95% CI) at 100 days post-HCT | NE | 97 (87–100) | 100 | 100 | 99 (95–100) | 98 (95–100) | 0.8543 |
| OS (95% CI) at 1 year post-HCT | NE | 97 (87–100) | 97 (87–100) | 94 (87–98) | 95 (88–99) | 93 (87–97) | 0.8998 |
| Subgroup analysis Age 40–59 yrs at time of HCT | |||||||
| Number of patients | 218 | 384 | 505 | 961 | 1391 | 1748 | |
| OS (95% CI) at 100 days post-HCT | 97 (95–99) | 97 (95–98) | 96 (94–98) | 97 (96–98) | 98 (97–99) | 99 (98–99) | 0.0028 |
| OS (95% CI) at 1 year post-HCT | 85 (80–89) | 85 (81–89) | 88 (85–91) | 91 (89–93) | 92 (90–93) | 93 (91–94) | <0.001 |
| Subgroup analysis Age ≥60 yrs at time of HCT | |||||||
| Number of patients | 39 | 127 | 179 | 529 | 955 | 1337 | |
| OS (95% CI) at 100 days post-HCT | 92 (82–98) | 94 (90–98) | 94 (90–97) | 97 (95–98) | 97 (96–98) | 98 (97–99) | 0.045 |
| OS (95% CI) at 1 year post-HCT | 73 (57–86) | 79 (71–85) | 84 (78–90) | 89 (86–91) | 92 (90–93) | 91 (90–93) | <0.001 |
|
| |||||||
| MM in less than a Partial Remission (Minimum Response, Stable Disease, Resistant Disease) | All patients | ||||||
| Number of patients | 105 | 177 | 392 | 420 | 521 | 586 | |
| OS (95% CI) at 100 days post-HCT | 92 (85–96) | 94 (90–97) | 96 (94–98) | 96 (94–98) | 97 (95–98) | 95 (93–97) | 0.3829 |
| OS (95% CI) at 1 year post-HCT | 79 (70–87) | 79 (73–85) | 86 (82–89) | 88 (84–91) | 88 (85–91) | 87 (84–90) | 0.0857 |
| Subgroup analysis Age 40–59 yrs at time of HCT | |||||||
| Number of patients | 68 | 122 | 257 | 248 | 302 | 300 | |
| OS (95% CI) at 100 days post-HCT | 92 (84–97) | 94 (89–98) | 96 (93–98) | 95 (92–97) | 97 (95–99) | 98(97–99) | 0.0751 |
| OS (95% CI) at 1 year post-HCT | 77 (65–87) | 83 (75–89) | 86 (81–90) | 86 (81–90) | 89 (85–93) | 88 (83–91) | 0.2728 |
| Subgroup analysis Age ≥ 60 yrs at time of HCT | |||||||
| Number of patients | 28 | 42 | 117 | 161 | 194 | 269 | |
| OS (95% CI) at 100 days post-HCT | 88 (73–98) | 90 (80–97) | 97 (93–99) | 97 (94–99) | 95 (92–98) | 91 (87–94) | 0.0478 |
| OS (95% CI) at 1 year post-HCT | 79 (60–93) | 66 (51–79) | 83 (74–89) | 91 (85–95) | 85 (80–90) | 85 (80–90) | 0.0272 |
NE= not evaluable, sample size < 25 patients in this subgroup.
Subgroup analyses by age are presented for the highest frequency groups
DISCUSSION
AutoHCT continues to be a treatment option primarily for the management of hematologic disorders. Utilization of autoHCT remained more or less stable for AML, HL and NHL during our study time period and mirrored the increase in incidence for these diseases in the general population. However, its use for ALL decreased and its utilization for MM increased substantially. It is still utilized for less common, non-hematologic disorders such as neuroblastoma, central nervous system (CNS) tumors and relapsed testicular cancer. The use of autoHCT for breast cancer treatment, either for adjuvant or metastatic disease, has essentially stopped.5 This is likely due to the lack of evidence for the superiority of autoHCT over lower dose therapy in several randomized trials. The decrease in the number of centers reporting autoHCTs to the CIBMTR during the time period of our study relates to the reduction in autoHCTs for breast cancer, since several centers performed autoHCT only for breast cancer.
There has been limited growth in the utilization of autoHCT for autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, systemic sclerosis and multiple sclerosis. This may be due to initial high morbidity and mortality rates associated with autoHCT as well as the availability of new treatment agents such as infliximab and etanercept for rheumatoid arthritis and inflammatory bowel disease, and interferon β-1a and β-1b, glatiramer acetate, natalizumab, and fingolimod for multiple sclerosis.
The story is different for MM patients. In 1996, the first randomized trial demonstrated the improvement in response rate, event-free survival and OS for MM patients receiving an autoHCT when compared to lower dose chemotherapy.2 Since then, our data demonstrate a 5-fold increase in the total number of autoHCTs for MM and a 20-fold increase in the number of autoHCTs as part of initial therapy in 1st CR or PR. For MM patients, randomized clinical trials of HCT versus novel therapy agents are underway to determine if there is a more specific role for autoHCT as part of upfront therapy for MM. Conversely, autoHCT may allow MM patients to have less exposure to prolonged therapy due to a greater depth of response with autoHCT compared to novel agents, as preliminary reports have demonstrated.14 Consolidation and maintenance strategies incorporating novel agents (bortezomib and lenalidomide) along with autoHCT have been shown to improve survival, although more research is still needed in this area especially given the risks (e.g., secondary cancers with lenalidomide) and costs of such an approach.15–17
The number of autoHCTs for NHL and HL patients has increased despite a decrease in the number of reporting autologous transplant centers. Rituximab received FDA approval in 2006 for use as part of upfront therapy for diffuse large cell and low grade/follicular NHL.18 The use of rituximab early in NHL treatment has affected outcomes for those who relapse, especially within a year of completion of upfront therapy.8 The latter patient population does poorly and may not go to autoHCT due to refractory disease. Since our study population ends in 2005, it is not known how the use of rituximab outside of clinical trials might impact on utilization of autoHCT for NHL or overall survival. However, our results demonstrate no significant improvement in overall survival over time in patients with refractory NHL, demonstrating the need for newer agents and approaches such as maintenance therapy for high risk patients.
Nearly half of all autoHCT performed since 2000 have been for patients older than 50 years of age. This has several implications. Since there is a higher incidence of cancer in older individuals, and the US and Canadian populations have increased in age,19 use of autoHCT for cancer treatment in the older (>50) adult population is likely to expand. Further, in this study MM and NHL patients over the age of 40 and with chemotherapy-responsive disease have experienced the greatest improvement in day 100 and 1 year OS. The reasons for this improvement may be multi-factorial, reflecting improvements in patient selection, identification of transplant candidates early in the course of disease, better supportive care, and better definition of optimal dose-intensive regimens. As an example, total body irradiation containing regimens for lymphoma and myeloma, associated with higher toxicity without improved outcomes, were more common in the earlier cohorts, but were seldom used in the later cohorts of our study.3
Many factors can influence a patient’s and physician’s decision regarding use of autoHCT for therapy, including age, disease and remission status, co-morbidities, caregiver support, insurance coverage, referring physician willingness to refer the patient and timing of patient referral for HCT consultation. While data were not available in this study to determine factors that influenced the practice patterns, inferences can be made based on clinical practice guidelines and improved patient outcomes. Indeed, better outcomes positively influence decision-making regarding transplant referral. While significant progress has been made in early (Day 100) survival rates, additional improvements are still needed to decrease disease progression and relapse post-transplantation to further improve long-term disease control and cure rates.
Acknowledgments
Funding Sources
This study had no specific funding or grant support. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 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 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; 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, or any other agency of the U.S. Government.
Footnotes
This study was presented in part at the American Society of Hematology annual meeting 2010 and published as an abstract [McCarthy PL, Hahn T, Hassebroek A, et al. Significant improvement in Day 100 and 1-year overall survival in patients who underwent autologous hematopoietic cell transplant in the US or Canada between 1994 and 2005. Blood 116:2010. (abstr 2389)] and at the American Society of Blood and Marrow Transplantation annual meeting 2010 and published as an abstract [Hahn T, McCarthy PL, Hassebroek A, et al. Transplant utilization, procedure patterns and patient characteristics in North American transplant centers from 1994–2005. Biol Blood Marrow Transplant 16: 2010. (abstr 113)]
Authorship Contributions
Navneet Majhail had full access to all of the data in the study and had final responsibility for the integrity of the data, the accuracy of the data analysis, and the responsibility for the decision to submit for publication.
Authors designed research (all authors), collected data (NM, AH), performed statistical analysis (PM, TH, AH, NM), interpreted data (all authors), drafted the manuscript (PM, TH, NM), and critically revised the manuscript (all authors). All authors have reviewed and approved the final version of the manuscript.
There are no relevant financial disclosures or conflicts-of-interest for any authors related to this work.
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.Pasquini MC, Wang Z. [Accessed April 18, 2011];Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. 2010 Available at: http://www.cibmtr.org.
- 2.Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91–97. doi: 10.1056/NEJM199607113350204. [DOI] [PubMed] [Google Scholar]
- 3.Salar A, Sierra J, Gandarillas M, et al. Autologous stem cell transplantation for clinically aggressive non-Hodgkin’s lymphoma: the role of preparative regimens. Bone Marrow Transplant. 2001;27(4):405–412. doi: 10.1038/sj.bmt.1702795. [DOI] [PubMed] [Google Scholar]
- 4.Farquhar C, Majoribanks J, Lethaby A, Basser R. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev. 2007;33(4):325–337. doi: 10.1016/j.ctrv.2007.01.007. [DOI] [PubMed] [Google Scholar]
- 5.Howard DH, Kenline C, Lazarus HM, et al. Abandonment of high-dose chemotherapy/hematopoietic cell transplants for breast cancer following negative trial results. Health Serv Res. 2011;46(6pt1):1762–1777. doi: 10.1111/j.1475-6773.2011.01296.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ledermann JA. Lessons learned from a decade of clinical trials of high-dose chemotherapy in ovarian cancer. Int J Gynecol Cancer. 2008;18(suppl 1):53–58. doi: 10.1111/j.1525-1438.2007.01107.x. [DOI] [PubMed] [Google Scholar]
- 7.Bensinger W. Stem-cell transplantation for multiple myeloma in the era of novel drugs. J Clin Oncol. 2008;26(3):480–492. doi: 10.1200/JCO.2007.11.6863. [DOI] [PubMed] [Google Scholar]
- 8.Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–4190. doi: 10.1200/JCO.2010.28.1618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117(23):6063–6073. doi: 10.1182/blood-2011-02-297325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. [Accessed on 4/19/11];National Coverage Determination (NCD) for Stem Cell Transplantation (110.8.1). Version 5, effective 8/4/10. Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=45&ncdver=5&bc=BAAAgAAAAAAA&.
- 11. [Accessed on 4/19/2011];CareFirst BlueCross BlueShield Medical Policy 7.03.003 High dose chemotherapy/radiation therapy with allogeneic stem cell support. Last revised 5/24/2010. http://notesnet.carefirst.com/ecommerce/medicalpolicy.nsf/vwwebtablex/71e6ebb6f3d7f1d38525772d004248b8?OpenDocument.
- 12.Cigna Medical Coverage Policy. [Accessed on 4/19/2011];Stem-cell transplantation for myelodysplastic syndromes. Effective Date 10/15/2010. http://www.cigna.com/customer_care/healthcare_professional/coverage_positions/medical/mm_0187_coveragepositioncriteria_stem_cell_transpl_myelodysplastic_syndr.pdf.
- 13.Cigna Medical Coverage Policy. [Accessed on 4/19/11];Stem-cell transplantation for multiple myeloma and POEMS. Effective Date 4/15/2011. http://www.cigna.com/customer_care/healthcare_professional/coverage_positions/medical/mm_0294_coveragepositioncriteria_stem_cell_transpl_mult_myeloma_poems.pdf.
- 14.Palumbo A, Cavallo F, Lupo B, et al. Melphalan/prednisone/lenalidomide (MPR) versus high dose melphalan and autologous transplantation (Mel200) in newly diagnosed multiple myeloma patients: A Phase III Study. Haematologica. 2011;96:214–15. [suppl2, abstr 508] [Google Scholar]
- 15.Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–948. doi: 10.1182/blood-2011-09-379164. [DOI] [PubMed] [Google Scholar]
- 16.McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–1781. doi: 10.1056/NEJMoa1114083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hari PN, McCarthy PL. Multiple myeloma: Future directions in autologous transplantation and novel agents. Biol Blood Marrow Transplant. 2013;19 (Suppl 1):S20–25. doi: 10.1016/j.bbmt.2012.11.002. [DOI] [PubMed] [Google Scholar]
- 18. [Accessed on 1/9/12];FDA approval for rituximab. Available at: http://www.cancer.gov/cancertopics/druginfo/fda-rituximab/print.
- 19.Characteristics of our aging population. [Accessed on 09/20/2011]; Available at: http://transgenerational.org/aging/demographics.htm.