Haematologica 2002; 87:(12)ECR41
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Clinical and molecular remission following reduced intensity conditioning and allogeneic transplantation in a patient with refractory multiple myeloma
Anna Dodero,* Vittorio Perfetti,° Fabio Ciceri,# Paolo Corradini*
*Ematologia, Unita' di Trapianto di Midollo Osseo, Istituto Nazionale dei Tumori, Università di Milano, Italia; °Dipartimento di Medicina Interna, Universita' di Pavia-IRCCS Policlinico San Matteo, Pavia; #Unita' di Trapianto di Midollo Osseo, Istituto Scientifico San Raffaele, Milano, Italia.
Correspondence: Dr. Anna Dodero, M.D., Hematology, BMT Unit, Istituto Nazionale dei Tumori, Via Venezian 1, 20132 Milano, Italia. E-mail:anna.dodero@istitutotumori.mi.it

High-dose chemotherapy followed by autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT) is routinely used for the treatment of myeloma patients. In the autologous setting, however, overall and progression-free survival at 10 years after transplantation are 30% and 16% respectively.1 The procedure is not considered curative because of the high relapse rate (70-84%). In addition there are only anecdotal reports of patients attaining clinical and molecular remission after auto-HSCT (7-16%).2,3
In the allogeneic setting, about 50% of patients attain a complete remission (CR), and 30 to 50% of them remain disease free 3 to 6 years after transplantation.4 Continuous molecular remissions have been described in a fraction of patients in CR after allo-HSCT.2,3,5 The clinical and molecular remissions obtained have been largely attributed to the postulated graft-versus-myeloma effect (GVM). Further support for the existence of a GVM effect comes from remissions obtained with donor lymphocyte infusion (DLI) in patients relapsed after T-depleted allografting.6 However, the curative potential of allo-HSCT is frequently offset by the the high transplant-related-mortality (TRM), for such a reason, programs employing reduced-intensity conditioning (RIC) have been developed. Here, we report a case of clinical and molecular remission in a patient with refractory MM experiencing an early disease progression after RIC allo-HSCT.
Case Report and Methods. A 53-year old man was diagnosed with MM (light chain isotype k), stage III A according to Durie-Salmon in August 1999. At time of diagnosis elevated b-2-microglobulin (4.78 mg/L) and C-reactive protein (40 mg/l), bone marrow infiltration with >90% atypical plasma cells were present as adverse prognostic factors (conventional karyotyping was performed and showed a t(1;4) translocation). He was treated with four VAD courses (vincristine, doxorubicin, dexamethasone) with minimal response; then, he received cyclophosphamide 7 g/m2, followed by G-CSF to mobilize autologous peripheral blood stem cells. In June 2000 he received melphalan 200 mg/n2 followed by auto-HSCT. On 2 October 2000 (412 days from diagnosis), he was in partial remission and received an allo-HSCT from his HLA-identical sister. The RIC regimen consisted of thiotepa (5 mg/kg) once daily i.v. on days -6, cyclophosphamide (30 mg/n2) and fludarabine (30mg/ms) once daily i.v. on days -4 and -3 and thymoglobulin (2.5 mg/kg) once daily i.v. on days -2, -3. Cyclosporine (CyA) (2 mg/kg) from day-2, short course methotrexate (10 mg/ms on day +1 and 8 mg/ms on days +3 and +6) were given for GVHD prophylaxis. Donor blood peripheral stem cells were mobilized using lenograstim 10 mg/kg/die for five days. The graft composition was as follows: 6.6x108/Kg mononuclear cells, 5.1¥106 /Kg CD34+ and 1.4x108/Kg CD3+. Engraftment was prompt: more than 500/mL neutrophils on day 12, and platelet> 20000/mL on day 14. There were no infectious complications and no mucositis, the patient was discharged on day 17. The disease was stable one month after allo-HSCT and hematopoietic chimerism was not tested. Evaluation at two months after allo-HSCT showed myeloma progression: proteinuria was 1.2 g/24h and marrow plasmocytosis was 36%. Hematopoietic chimerism was assessed by marrow cytogenetics and showed mixed chimerism with 22% of recipient cells. A delayed recovery of T-cell numbers was observed: median CD4+ and CD8++ at day +60 were 95/mL and 168/mL respectively.
Because of disease progression, CyA was tapered by 20% every 10 days. During CyA reduction we observed a decrease of Bence-Jones proteinuria (Figure 1) and a stable number of bone marrow plasma cells; on day +180 CyA administration was stopped. On day +256 the patient developed extensive chronic GVHD involving skin, oral mucosa, liver. Evaluation of disease at GVHD onset showed a clinical remission. The CR occurred with the attainment of full donor chimerism. After two weeks (on day +271) we started GVHD treatment with methylprednisone and reinstitution of CyA with resolution of GVHD symptoms. The evaluation on days +309, +480, +650, and +767 showed a continuous CR. A seminested allele-specific oligonucleotide polymerase-chain-reaction (ASO-PCR) strategy based on rearranged immunoglobulin lights-chain genes of bone marrow cells was performed at these timepoints showing a picture of molecular remission.7
Discussion. The patient reported herein experienced an early progression after allograft but was reinduced into complete clinical and molecular remission after withdrawal of immunosuppressive therapy. While molecular complete remission (MCR) can be achieved in 30 to 50% of patients receiving conventional allograft, MCR reports following RIC allo-HSCT are limited. Garban et al.8 described the attainment of MCR in 2 of 12 cases but no follow-up details were given. In our patient, we obtained a sustained MCR (molecular follow-up: 15 months) after RIC. Even though the relationship between achievement of MCR and cure in MM is still under investigation, several data from Martinelli et al.3 suggest that PCR-negativity correlates with prolonged relapse-free survival (110 versus 35 months; p< 0.05).
Strategies to treat disease recurrence/progression after allografting include immunesuppression withdrawal and/or DLI. So far, remission-inducing effects of immunosuppression withdrawal have never been systematically studied in MM patients progressing after allograft. In our patient seventy-six days without immunosuppression were sufficient to elicit a GVM effect and to obtain full donor chimerism. The antimyeloma effect was associated with the occurrence of GVHD. MCR has been reported after DLI for recurrence/progression, especially after T-cell depleted (TCD) allografts. Lokhorst et al.6 reported 22% CR with two sustained MCR in MM patients relapsing after partial TCD allograft. DLI, however, were associated with relevant toxicity: 55% acute GVHD, and 11% TRM. Recently, Badros et al.9 reported 61% CR/nearCR in MM patients with high risk disease receiving high-dose melphalan followed by allo-HSCT. Other studies10,11 with different RIC regimens (Table 1) have reported complete responses ranging from 25% to 50%. Complete remission was usually associated with chemosensitive disease and occurrence of GVHD.
In conclusion, this report shows that a sustained MCR can be achieved even after RIC allografting with a GVM effect occurring after withdrawal of immunosuppression and with a concomitant flare of GVHD.

References

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