The reduced intensity conditioning regimen described is feasible, well tolerated in heavily pre-treated patiens. An objective response was obtained in 80% of the patients, 30% achieved a complete response

Arana, MG

Bacigalupo, A

Corradini, P.

De Fabritiis, P

Di Bartolomeo, P

Locasciulli, A

Majolino, I

Narni, F

OLIVIERI, Attilio

Riccardi, M

Scime, R

English

IRIS UniversitÃ  Politecnica delle Marche

Reduced intensity conditioning with thiotepa, fludarabine and melphalan for allogeneic transplantation in multiple myeloma.

Reduced-intensity conditioning with thiotepa, fludarabine and melphalan for allogeneic transplantation in multiple myeloma

I. Majolino

K. P. Urago

M. Riccardi

A. Locasciulli

A. Bacigalupo

P. Di Bartolomeo

R. Scimè

A. Olivieri

NARNI, Franco

P. Corradini

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

96 Haematologica/journal of hematology vol. 88(suppl. 10):May 2003nation.10 A rapid reduction of the M component, withdisappearance of the marrow plasma-cell infiltrationhas been documented late after allo-SCT, at the timeof chronic graft-versus-host disease (GVHD) onset.7Design and methodsFor patients with MM we have recently designed aprogram of reduced-intensity conditioning transplantfrom HLA-identical sibling donors. The conditioningcombines fludarabine, thiotepa and melphalan (Figu-re 1). GVHD prophylaxis is based on methotrexate-cyclosporine, but the latter is rapidly tapered fol-lowing transplantation to favor the emergence of animmune-mediated suppression of tumor. DLI areemployed in those patients who remain GVHD-freebut still harbor detectable tumor following cyclospo-rine tapering. The study is supported by a molecularanalysis of bone marrow cells to detect IgH genemutation as a marker of miminal residual disease.4ResultsTwenty patients have been enrolled so far. We havedata on 18 of them. Their characteristics are reportedin Table 1. Seven were transplanted early in the cour-se of their disease, while 11 had the allograft as treat-ment for disease progression or relapse. As transplant,they received a median of 5.1×106/Kg CD34+ cells(range 0.2-10.2), and 3.0×108/Kg CD3+ cells (range0.4- 4.2) from bone marrow or granulocyte colony-stimulating factor (G-CSF)-primed peripheral blood.Full engraftment occurred in all, with 14 days to reco-ver >0.5×109/L granulocytes  (range 10-18) and 12days to recover  >20×109/L platelets (range 4-22).Acute GVHD is evaluable in 16. Grade 1 GVHDdeveloped in 4, grade 2 in 3 (18%). None developedgrade >2 acute GVHD. Of the 11 patients evaluable,6 (54%) developed chronic GVHD. Clinical resultsare summarized in Table 2. Thirteen patients are eva-luable for transplant response. Three of them werealready in complete remission (CR) at the time oftransplantation. Another 2 achieved CR after the allo-graft, while 6 reached only a partial remission and 2were refractory.  Twelve patients are currently in fol-low-up, since 1 died of disease progression soon aftertransplantation. Until now there has been a singlerelapse. Four patients remain in CR at a median of 12months follow-up (range 5-15 months).In multiple myeloma (MM), high-dose therapy fol-lowed by single or autologous stem cell transplan-tation (auto-SCT) represents the treatment ofchoice for patients <60 years of age.1,2 However, auto-SCT is not able to eradicate the disease. In a retro-spective study of GITMO the event-free survival afterauto-SCT failed to show a plateau. In practice, allpatients relapsed within 3-5 years and later becameresistant to any available treatment. In the meantime,molecular biology studies confirm that the myelomacell clone seldom disappears after autologous tran-splantation.3,4 The reason is the persistence of a sizea-ble number of neoplastic cells both in the patient andin the graft. Allogeneic stem cell transplantation (alloSCT) isemployed much less frequently than autologous tran-splantation, due in part to the limited availability ofHLA-identical donors and in part to the higher tran-splant-related mortality (TRM).5 Nonetheless, aretrospective study within the EBMT6 has documen-ted a TRM reduction over the last few years, as resultof better selection of patients and improvements intechnologies, as may be the preferential use of che-motherapy-based conditioning instead of total-bodyirradiation and the use of stem cells from the periphe-ral blood rather from bone marrow.7The emerging concept is that suppression of theneoplastic clone may be obtained (in selected disea-ses) even without a mega-dose of chemo-radiothe-rapy as administered in the traditional transplanta-tion regimens. An immunosuppressive protocol, incombination with the infusion of a large number ofstem cells, will ensure stable engraftment and pro-mote a graft-versus-tumor effect with little toxicity.8Such methodology is currently under evaluation in avariety of hematologic disorders, including MM.9MM is typically an immune-sensitive disease, as wit-nessed by the efficacy of donor-lymphocyte infusions(DLI) following allo-SCT and by the results of vacci-From the Hematology and BMT, S.Camillo-Forlanini Hospital, Rome(IM, KPU, AL), Hematology Department, S.Martino Hospital, Genoa(AB), BMT Center, Pescara (PDB), BMT Unit, “V.Cervello” Hospital,Palermo (RS), Hematology Clinic, Torrette Hospital, Ancona (AO),Hematology Service, University of Modena (FN), Transplant Unit,National Cancer Institute, Milan, Italy (PC).Correspondence: Dr Ignazio Majolino, Unità Operativa di Ematologia eTrapianti di Midollo Osseo, Azienda Ospedaliera S.Camillo-Forlanini,Circonvallazione Gianicolense 87, Rome, Italy. Phone: international+39.06.58704418. Fax: international +39.06.58704357.E-mail: imajolino@libero.itReduced intensity conditioning with thiotepa, fludarabine and melphalanfor allogeneic transplantation in multiple myelomaI. MAJOLINO, K. P. URAGO, M. RICCARDI, A. LOCASCIULLI, A. BACIGALUPO, P. DI BARTOLOMEO, R. SCIMÈ, A. OLIVIERI, F. NARNI, P.CORRADININew Insights in Hematology, Venice, Italy, May 15-18, 2003Haematologica/journal of hematology vol. 88(suppl. 10):May 2003 97Conclusions and commentsThe preliminary results of the present protocolshow that reduced-intensity conditioning withfludarabine, thiotepa and melphalan is well tole-rated even in patients who have a long diseasehistory or who have had previous autograft(s). Infact, no patient died of transplant-related com-plications. For this reason this scheme seems tobe applicable also in elderly patients, or when co-morbidities would discourage the use of tran-splantation.In terms of GVHD, our experience is encoura-ging. Acute GVHD ≥ grade 2 occurred in lessthan 20% of patients and we did not observe gra-de 3 or 4. Chronic GVHD is expected to occur inTable 1. Patients’ characteristics.Patients (No.) 18Age (years) median 53 (21-64)Disease phaseearly 7advanced 11Previous autotransplant (No.) 10Time from diagnosis to allo (months) median 8 (3-66)Table 2. Clinical results.No. patientsEvaluable 13In CR at transplantation 3Evaluable for response to transplant 10CR 2PR 6NR 2In CR following transplantation 5 (38.4%)In follow-up 12Continuous CR 4Relapse 1Death 1Design of the protocol.New insights in Hematology, Venice, May 15-18, 200398 Haematologica/journal of hematology vol. 88(suppl. 10):May 2003over 50% of cases, but this is not to be envisagedas a negative factor in a disease that is known tobe sensitive to immune aggression.Our protocol is able to induce a response in asizeable proportion of patients. Eighty percentshowed a response, with over 30% CR. Of the 5patients in CR after transplantation only one hasrelapsed. The follow-up is, however, too short todraw any conclusions on remission duration.Data on IgH-gene rearrangement will be availa-ble in the next months, and will probably shedmore light on the significance of CR after thistreatment program.In conclusion, the reduced-intensity conditio-ning transplant presented here is considerablyless toxic than conventional conditioning. Theincidence of acute GVHD is limited, and clinicalresults appear to be encouraging, as nearly 30%of patients achieve a complete remission and themajority maintain this status, at least in theshort-term. We currently offer this program topatients with an HLA-identical sibling donor atthe time of induction, after 3-4 courses of VAD.FundingThe present work is in part supported by theAssociazione Italiana per la Ricerca sul Cancro(AIRC).References1. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG,Rossi JF, et al. A prospective, randomized trial of autol-ogous bone marrow transplantation and chemotherapyin multiple myeloma. Intergroupe Français du Myelome.N Engl J Med 1996;335:91-7.2. Attal M, Harousseau JL, Facon T. Double autologoustransplantation improves survival of multiple myelomapatients: final analysis of a prospective randomizedstudy of the "Inter Groupe Français du Myelome".Blood 2002; 100 Suppl 1:5a[abstract].3. Majolino I, Vignetti M, Meloni G, Vegna ML, Scime R,Tringali S, et al. Autologous transplantation in multiplemyeloma: a GITMO retrospective analysis on 290patients. Haematologica 1999;84:844-52.4. Corradini P, Voena C, Tarella C, Astolfi M, Ladetto M,Palumb, et al. Molecular and clinical remissions in mul-tiple myeloma: the role of autologous and allogeneictransplantation of hematopoietic cells. J Clin Oncol1999;17:208-15.5. Bensinger WI, Clift R, Martin P, Appelbaum FR, Demir-er T, Gooley, et al. Allogeneic peripheral blood stem celltransplantation in patients with advanced hematologicmalignancies: a retrospective comparison with marrowtransplantation. Blood 1996;88:2794-800.6. Gahrton G, Svensson H, Cavo M, Apperely J, BacigalupoA, Bjorkstrand B, et al. Progress in allogenic bone mar-row and peripheral blood stem cell transplantation formultiple myeloma: a comparison between transplantsperformed 1983-93 and 1994-8 at European Group forBlood and Marrow Transplantation centres. Br J Haema-tol 2001;113:209-16.7. Majolino I, Corradini P, Scimè R. High rate of remissionand low rate of disease recurrence in patients with mul-tiple myeloma allografted with PBSC from their HLA-identical sibling donors. Bone Marrow Transplant 2003;in press.8. Slavin S, Nagler A, Naparstek E. Nonmyeloablative stemcell transplantation and cell therapy as an alternative toconventional bone marrow transplantation with lethalcytoreduction for the treatment of malignant and non-malignant hematologic diseases. Blood 1998;91:756-63.9. Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M,Fassas A, et al. Improved outcome of allogeneic trans-plantation in high-risk multiple myeloma patients afternonmyeloablative conditioning. J Clin Oncol 2002;20:1295-303.10. Bellucci R, Alyea EP, Weller E, Chillemi A, Hochberg E,Wu CJ, et al. Immunologic effects of prophylactic donorlymphocyte infusion after allogeneic marrow trans-plantation for multiple myeloma. Blood 2002;99:4610-7.

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Reduced intensity conditioning with thiotepa, fludarabine and melphalan for allogeneic transplantation in multiple myeloma.

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