Haematologica 2003 - Supplements
Haematologica 2003 - Supplements Haematologica 2003 - Supplements
patients had 100% engraftment of donor cells (including 4 recipients of unrelated donor grafts). One patient died before day 30 from tumor lysis and toxicity. Seven patients achieved complete remission, and 5 failed to respond. At the time of the report 6 patients were alive between 3 and 24 months after transplant (median, 18 months), two in continued complete remission. The major causes of treatment failure in this group of refractory and heavily pretreated patients was GVHD (n=4) and disease (n=2) Thus engraftment of allogeneic progenitor cells after non myeloablative therapies is feasible in patients with myeloma, and further exploration of this strategy in patients with less advanced disease is warranted. The Seattle group has pioneered an innovative approach to nonablative transplantation using low dose TBI at a dose of 200 cGy in a single fraction in conjunction with post transplant immune suppression with cyclosporine and mycophenolate mofetil. (14) In the initial experience patients with myeloma and CML who had not received prior intensive therapy had a high risk of graft rejection and autologous reconstitution of over 20%. (15) To improve upon these outcomes, the Seattle group explored the safety and efficacy of high dose melphalan with autologous stem cell support followed 90-120 days by a non ablative preparative regimen of 200 cGy of TBI followed by an allogeneic peripheral blood stem cell infusion from an HLA identical sibling for myeloma patients who had never received a prior autograft. Twelve patients were treated with a median age 49 years (42-63) with a median time to transplant of 12 months (range, 4-57 months). Toxicity from the allografting was minimal with a median of 0 days of neutropenia (range, 0-10) and a median nadir neutrophil count of 760 neutrophils/l (range, 150-1270 neutrophils/l. All patients had donor cell engraftment with a median percentage of donor cells of 82%. Six patients developed grade III acute GVHD and 2 developed grade IV GVHD. Seven patients achieved a CR and 3 patients have died, 9 patients were alive with a median follow up of 7 months at the time of the report. (16) Further evidence for the role of non-ablative preparative regimens for multiple myeloma is provided by the number of papers presented in the 42 nd Annual Meeting of the American Society of Hematology (Table 1). Table 1: Other Non Ablative Stem Cell Transplant Trials with >10 Myeloma Patients Reported at the 42 nd Annual Meeting of the American Society of Hematology. Ref N Age Regimen Graft Failure NRM PFS 16 50 48 (33-62) 17 23 47 (34-58) 18 22 54 (32-66) 19 16 57 (42-70) FM:25 FB:17 FM- Campath FC-200 cGy NS Good Risk 10% Poor Risk 20% 0 17% @ 1yr 1 27% @ 100d Mel 100 1 3/16 Good Risk 80% Poor Risk 27% 42% @ 1yr Of interest among the papers presented are the results reported to the EBMT in which patients with good risk disease (chemosensitive relapse or remission consolidation) had a 10% non relapse mortality and a progression free survival of 80%. (17) In all reported series to date GVHD is an important cause of treatment failure. The use of pretransplant CAMPATH 1H has been reported to decrease the incidence of this complication, according to the experience reported by Peggs et al. (18) Melphalan at a lower dose of 100 mg/m 2 has also been used as a preparative regimen for non-ablative or reduced intensity conditioning. This dose as reported by the University of Arkansas group results in high rates of engraftment and low incidence of toxicity in patients who relapsed after either one or two autologous transplants. (19,20) All studies to date have demonstrated that chemosensitivity as well as extent of prior therapies are important prognostic factors for outcomes with few patients with refractory disease obtaining long term disease control. SUMMARY: The goals of therapy for myeloma have changed substantially from the initial days of melphalan and prednisone. (21) The advent of autologous transplant, and the recognition of the graft versus myeloma effect make it possible to search for complete remission and long term disease control in a substantial proportion of myeloma patients. However, the ability to exploit the graft versus myeloma effect has been hampered by the high incidence of transplant related mortality seen in the myeloma population. Reducing the intensity of the preparative regimen has been explored as a strategy to improve the outcomes of allogeneic transplant in myeloma. The results of the limited experience to date demonstrate that non-ablative and reduced intensity conditioning regimens are feasible in myeloma. This procedure results in donor cell engraftment, acceptable toxicity, and long term disease control in a fraction of patients. However, graft versus host disease and disease recurrence particularly in patients with relapsed or refractory disease continue to be the major obstacles to overcome. Further studies will be needed to define the role of reduced intensity and non-ablative conditioning in the treatment of multiple myeloma. REFERENCES 1. Tricot G, Vesole D, Jagannath S, Hilton J, Munshi N. Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood 87:1196-8, 1996. 2. Lokhorst H, Schattenberg A, Cornelissen J, Thomas L, Verdonck L: Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. 90:4206-11, 1997. 3. Salama M, Nevill T, Marcellus D, et al: Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 26:1179-84, 2000. 4. Gahrton G, Svensson H, Bjorkstrand B, et al: Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 24:741-5, 1999. 5. Bjorkstrand B, Ljungman P, Svensson H, et al: Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective casematched study from the European Group for Blood and Marrow Transplantation. Blood 88:4711-8, 1996. 6. Ringden O, Horowitz M, Gale R, et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults JAMA 270:57-60, 1993. 7. Cahn J, Labopin M, Mandelli F, et al: Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: A retrospective analysis of the European Bone Marrow Transplant Group. Blood 85:575-579, 1995. 8. Gale R, Bortin M, Van Bekkum D, et al: Risk factors for acute graft versus host disease Br. J Haematol 67:397-406, 1987 S70
9. Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analogcontaining chemotherapy: Harnessing graft versus-leukemia without myeloablative therapy. Blood 89:4531-6, 1997. 10. Slavin S, Nagler A, Naparstak E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non malignant hematologic diseases. Blood 91:756-63, 1998. 11. Khouri I, Keating MJ, Korbling M, et al.: Transplant lite: Induction of graft vs malignancy using fludarabine based nonablative chemotherapy and allogeneic progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-24, 1998. 12. McSweeney P, Niederwieser D, Shizuru J, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390- 3400, 2001 13. Giralt S, Weber D, Cohen A, et al: Non-myeloablative conditioning with fludarabine (F)/melphalan (M) for patients with multiple myeloma (MM). Proceedings of the American Society of Clinical Oncology 35th Annual Meeting. 18:6a (Abstract #18) 14. Molina A, Sahebi F, Maloney D, et al. Non-myeloablative peripheral blood stem cell allografts (PBSC) following cytoreductive autotransplants for treatment of multiple myeloma (MM). Blood 96:480a, 2000. 15. Maloney D, Sahebi F, Stockerl-Goldstein K, et el: Combining an allogeneic graft vs myeloma effect with high dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 98:434a, 2001. 16. Lalancette M, Rezvani K, Szydlo R, et al. Excellent outcome of non-myeloablative stem cell transplant (NMSCT) for good risk myeloma: The EBMT experience. Blood 96:204a, 2000. 17. Peggs K, Williams C, Chopra R, et al. Non-myeloablative allogeneic transplantation with adjuvant dose escalated donor lymphocyte infusions for multiple myeloma. Blood 96:781a, 2000. 18. Schaefer H, Bader P, Hebart H, et al. Mini-allografts as salvage therapy in patients with heavily pretreated multiple myeloma. Blood 96:306b, 2000. 19. Badros A, Tricot G, Morris C, et al. Significant graft vs myeloma effect after non-myeloablative allogeneic transplantation in multiple myeloma Blood 96:352b, 2000 20. Badros A, Barlogie B, Siegel D, et al: Improved outcome of allogeneic transplantation in high risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20:1295-1303, 2002 21. Alexanian R, Dimopoulos A: Drug Therapy: The treatment of multiple myeloma N Engl J Med 330:484-489, 1994 P11.2.3 HIGH DOSE THERAPY VERSUS CONVENTIONAL CHEMOTHERAPY FOR NEWLY DIAGNOSED MULTIPLE MYELOMA: HISTORICAL COMPARISON OF TOTAL THERAPY I VERSUS STANDARD SWOG TRIALS AND US INTERGROUP TRIAL SWOG 9321. Bart Barlogie, Joth Jacobson, Kenneth Anderson, Philip Greipp, Robert Kyle and John Crowley. The Myeloma Institute for Research and Therapy (MIRT), University of Arkansas for Medical Sciences, Little Rock, AR , USA; Cancer Research And Biostatistics (CRAB), Fred Hutchinson Cancer Center, Seattle, WA , USA; Mayo Clinic, Rochester, MN; Dana Farber Cancer Institute, Harvard Medical Center, Boston, MA. Improved long-term survival of patients with myeloma is directly linked to the widespread use of high-dose melphalan usually at 200mg/m 2 (MEL 200) with peripheral blood stem cell support (PBSC). Since mucositis is dose-limiting, tandem transplants were evaluated in TT I to further augment cell kill toward increasing CR and extending event-free and overall survival. Of 231 patients enrolled between 1989 and 1994, 152 were previously entirely untreated and could be closely matched with 152 contemporaneous patients receiving standard dose therapies (SDT) as part of SWOG trials (matching criteria included age, B2M, albumin). No significant differences existed in the proportions of patients with IgA isotype and creatinine >2mg/dL (Table 1). With a median follow-up of 10 years for all patients, 10-year survival and event-free survival rates were markedly higher with TT I than with SWOG SDT (33 vs 15%, p
- Page 25 and 26: P2.5 MOLECULAR CYTOGENETICS OF MYEL
- Page 27 and 28: clear that the biggest challenge fo
- Page 29 and 30: esponse and have demonstrated that
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- Page 55 and 56: presumably through the circulation,
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- Page 73 and 74: found that 75% of patients who were
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- Page 83 and 84: improve patient outcome in MM. Impo
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- Page 91 and 92: myeloma. Blood 2001; 98:210-216. 6.
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- Page 119 and 120: 4 patients had MMSET/IgH but did no
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9. Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic<br />
hematopoietic progenitor cells with purine analogcontaining<br />
chemotherapy: Harnessing graft versus-leukemia<br />
without myeloablative therapy. Blood 89:4531-6, 1997.<br />
10. Slavin S, Nagler A, Naparstak E, et al. Nonmyeloablative<br />
stem cell transplantation and cell therapy as an alternative to<br />
conventional bone marrow transplantation with lethal<br />
cytoreduction for the treatment of malignant and non<br />
malignant hematologic diseases. Blood 91:756-63, 1998.<br />
11. Khouri I, Keating MJ, Korbling M, et al.: Transplant lite:<br />
Induction of graft vs malignancy using fludarabine based<br />
nonablative chemotherapy and allogeneic progenitor-cell<br />
transplantation as treatment for lymphoid malignancies. J<br />
Clin Oncol 16:2817-24, 1998.<br />
12. McSweeney P, Niederwieser D, Shizuru J, et al:<br />
Hematopoietic cell transplantation in older patients with<br />
hematologic malignancies: replacing high-dose cytotoxic<br />
therapy with graft-versus-tumor effects. Blood 97:3390-<br />
3400, 2001<br />
13. Giralt S, Weber D, Cohen A, et al: Non-myeloablative<br />
conditioning with fludarabine (F)/melphalan (M) for patients<br />
with multiple myeloma (MM). Proceedings of the American<br />
Society of Clinical Oncology 35th Annual Meeting. 18:6a<br />
(Abstract #18)<br />
14. Molina A, Sahebi F, Maloney D, et al. Non-myeloablative<br />
peripheral blood stem cell allografts (PBSC) following<br />
cytoreductive autotransplants for treatment of multiple<br />
myeloma (MM). Blood 96:480a, 2000.<br />
15. Maloney D, Sahebi F, Stockerl-Goldstein K, et el:<br />
Combining an allogeneic graft vs myeloma effect with high<br />
dose autologous stem cell rescue in the treatment of multiple<br />
myeloma. Blood 98:434a, 2001.<br />
16. Lalancette M, Rezvani K, Szydlo R, et al. Excellent outcome<br />
of non-myeloablative stem cell transplant (NMSCT) for<br />
good risk myeloma: The EBMT experience. Blood 96:204a,<br />
2000.<br />
17. Peggs K, Williams C, Chopra R, et al. Non-myeloablative<br />
allogeneic transplantation with adjuvant dose escalated<br />
donor lymphocyte infusions for multiple myeloma. Blood<br />
96:781a, 2000.<br />
18. Schaefer H, Bader P, Hebart H, et al. Mini-allografts as<br />
salvage therapy in patients with heavily pretreated multiple<br />
myeloma. Blood 96:306b, 2000.<br />
19. Badros A, Tricot G, Morris C, et al. Significant graft vs<br />
myeloma effect after non-myeloablative allogeneic<br />
transplantation in multiple myeloma Blood 96:352b, 2000<br />
20. Badros A, Barlogie B, Siegel D, et al: Improved outcome of<br />
allogeneic transplantation in high risk multiple myeloma<br />
patients after nonmyeloablative conditioning. J Clin Oncol<br />
20:1295-1303, 2002<br />
21. Alexanian R, Dimopoulos A: Drug Therapy: The treatment<br />
of multiple myeloma N Engl J Med 330:484-489, 1994<br />
P11.2.3<br />
HIGH DOSE THERAPY VERSUS CONVENTIONAL<br />
CHEMOTHERAPY FOR NEWLY DIAGNOSED MULTIPLE<br />
MYELOMA: HISTORICAL COMPARISON OF TOTAL<br />
THERAPY I VERSUS STANDARD SWOG TRIALS AND<br />
US INTERGROUP TRIAL SWOG 9321.<br />
Bart Barlogie, Joth Jacobson, Kenneth Anderson, Philip<br />
Greipp, Robert Kyle and John Crowley.<br />
The Myeloma Institute for Research and Therapy (MIRT),<br />
University of Arkansas for Medical Sciences, Little Rock, AR ,<br />
USA; Cancer Research And Biostatistics (CRAB), Fred Hutchinson<br />
Cancer Center, Seattle, WA , USA; Mayo Clinic, Rochester, MN;<br />
Dana Farber Cancer Institute, Harvard Medical Center, Boston,<br />
MA.<br />
Improved long-term survival of patients with myeloma is directly<br />
linked to the widespread use of high-dose melphalan usually at<br />
200mg/m 2 (MEL 200) with peripheral blood stem cell support<br />
(PBSC). Since mucositis is dose-limiting, tandem transplants<br />
were evaluated in TT I to further augment cell kill toward<br />
increasing CR and extending event-free and overall survival. Of<br />
231 patients enrolled between 1989 and 1994, 152 were<br />
previously entirely untreated and could be closely matched with<br />
152 contemporaneous patients receiving standard dose therapies<br />
(SDT) as part of SWOG trials (matching criteria included age,<br />
B2M, albumin). No significant differences existed in the<br />
proportions of patients with IgA isotype and creatinine >2mg/dL<br />
(Table 1). With a median follow-up of 10 years for all patients,<br />
10-year survival and event-free survival rates were markedly<br />
higher with TT I than with SWOG SDT (33 vs 15%, p
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