Long-term results of the UHKT-911 study of adult patients under 65 years of age with de novo acute myeloid leukemias without favorable karyotypes

Between February 1991 and April 1994 induction chemotherapy of 32 adult consecutive patients under 65 years with de novo acute myeloid leukemias (AML) was started in the study UHKT-911. They were 19 women and 13 men, aged 18-63 (median 44) years. Their AML were classified according to the FAB classification: 3 M0, 3 M1, 9 M2, 14 M4, 3 M5. Induction chemotherapy consisted of 1-2 cycles with 3-4 doses of daunorubicin (DNR) 45 mg/m2/d i.v. and 14 doses of cytosine arabinoside (Ara-C) 200 mg/m2 per 3-h infusion every 12 hours. After the treatment patients, not being in complete remission, got the HD cycle with 10 high-doses of Ara-C 2000 mg/m2 per 3-h infusion every 12 hours i.v. and DNR 45 mg/m2/d i.v. on days 4 and 5, then the EMi cycle composed of etoposide 100 mg/m2/d i.v. for 5 days and mitozantrone 10-12 mg/m2/d i.v. on days 1, 3 and 5. Complete remission (CR) was achieved in 25 of 32 (78%) patients after 1-3 cycles. Five patients died between days 5 and 24 of treatment of infections, two patients were resistant to 4 cycles of induction therapy and survived 8.4 and 13.5 months. Three patients chose allogeneic bone marrow transplantation in their 1st CR from their relatives. Two of them have been living in CR for 115 a 110 months since diagnosis, the third died of sepsis on the day 52 after transplantation. Two patients in CR died of infections after their 2nd. consolidation cycle. Twenty patients in CR completed 2-4 consolidation cycles (1-3 HD, 1 EMi). Median of their CR duration was 17.8 (2-117) months. Relapse appeared in 12 cases after 4.4-34.8 (median 12.5) months, 8 patients (6 women and 2 men, aged 29-63 years) have remained longer than 5 years in their 1st. CR. Cytogenetic examination of their bone marrow showed a normal karyotype in 4 cases, 1x 46,XX,del(1)(p32p34), 1x 46,XX,16p+, 1x 47,XX,+mar, 1x 46,XX,del(5)(q22q33). After 62 months in CR a pancytopenia with dysplastic bone marrow changes developed in one of them, probably a secondary myelodysplastic syndrome, lasting for further 33 months. Event-free survival at 5 years was 27.5% (8/29 patients), significantly better (p = 0.046) against 7.5% (3/40) patients treated without HD cycles in the years 1982-1987. The same difference was observed in 7.5-year overall survival (p = 0.036) between the two studies, when 3 of 6 patients 60-64 years old remain in their 1. CR.     

Reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells from the same donor for relapsed leukemia after bone marrow transplantation

We report the clinical courses of two cases with relapsed acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT). After reinduction chemotherapy, the patients received reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells harvested from their previous BMT donors. The conditioning regimen used consisted of fludarabine and melphalan. Graft-versus-host disease (GVHD) prophylaxis was performed with low dose cyclosporin A (CsA, 1 mg/kg/day d.i.v.) on its own. The regimen related toxicity was minimal, and stable engraftment was achieved. Since acute GVHD had not developed by day 30, CsA was stopped abruptly in both cases. After CsA withdrawal, acute GVHD developed, and subsequent chronic GVHD. One of two cases is alive without any relapse of the leukemia 40 months after the peripheral blood stem cell transplantation (PBSCT). In the other case, ALL relapsed 15 months after the PBSCT, however, complete remission was again induced concomitantly with reactivated GVHD. In both these cases, the results suggest that using PBSC as a stem cell source and abrupt cessation of GVHD prophylaxis provided a potent graft-versus-leukemia effect.     

Occurrence of multiple myeloma in both donor and recipient after bone marrow transplantation

The transplantation of malignant cells during allogeneic transplant is a rare occurrence. 27 months after donating progenitor cells, a diagnosis of multiple myeloma was made in a 6/6 HLA-phenotypically matched unrelated donor. The 42-year-old recipient transplanted for chronic phase chronic myeloid leukemia developed IgA myeloma 40 months after transplantation. Serum electrophoresis and bone marrow investigations established the diagnosis of IgA K multiple myeloma in both. This case illustrates the natural history and biology of multiple myeloma.     

Primary plasma cell leukemia: report of 17 new cases treated with autologous or allogeneic stem-cell transplantation and review of the literature

Primary plasma cell leukemia (PPCL) is a rare hematologic malignancy characterized by the proliferation of plasma cells in blood, bone marrow, and other organs in the absence of established multiple myeloma. PPCL has a poor prognosis when treated with conventional therapy for multiple myeloma. We describe here 17 new cases of PPCL who underwent stem-cell transplantation (SCT) (2 cases observed by the authors and 15 cases from the International Bone Marrow Transplant Registry [IBMTR]). The first case was diagnosed in a 21-year-old male who presented with leukocytosis and acute renal failure. He was treated with hyper-CVAD, entered complete remission, and then proceeded to high-dose chemotherapy with peripheral stem-cell support. He is currently in complete remission 23 months after initial diagnosis and 19 months after autologous SCT. The second case was observed in a 31-year-old male who presented with leukocytosis and hepatic infiltration with plasma cells. He was treated with VAD chemotherapy and underwent allogeneic bone marrow transplantation from his HLA-identical sister. He remained in complete remission for 3 years and then developed progressive refractory disease, dying 7 years after the initial diagnosis. In addition to these 2 cases, 15 further unpublished cases of PPCL from the IBMTR are reported here (treated between 1993 and 2001, 6 by autologous and 9 by allogeneic transplantation). Finally, the features of PPCL, the outcome, published data of SCT for PPCL, and indications for treatment are discussed.     

Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.     

Unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia

Eight patients received allogeneic bone marrow transplantation (BMT) as therapy for chronic myelogenous leukemia (CML) using marrow from unrelated donors. In all cases donors and recipients were HLA DR identical and had low MLC reactivity. In three cases recipients received marrow that was identical at the HLA A,B loci. In five cases HLA identity differed for one HLA A locus antigen. The unrelated donor search interval ranged from 2 to 28 months (median, 3 months). All recipients were prepared with a combination of cyclophosphamide, 60 mg/kg/d administered intravenously (IV) (days -6,-5) and with total body irradiation administered in 165 cGy fractions twice daily for four days (days -4, -3, -2, -1). Engraftment occurred in all cases (range, 18 to 48 days; median, 35 days), and return to a complete Philadelphia chromosome (Ph') negative state was documented in six of eight cases. Moderate or severe acute graft v host disease (GVHD) occurred in seven of eight cases, and extensive chronic GVHD in four of six evaluable recipients. A B cell lymphoproliferative disorder developed in one patient. Four recipients have died within 2 to 4 months of transplant. Four of eight patients survive at 11+ to 24+ months following transplantation (median, 15+ months) with normal peripheral blood counts and without evidence of leukemia. Current Karnofsky activity assessments are 90% or 100% in all survivors. Curative therapy of CML has been available only to the minority of patients eligible for sibling donor BMT. Unrelated donor BMT can be effective in the treatment of CML and may be particularly useful in this disorder since the prolonged stable phase of disease offers an opportunity to locate suitable donors.     

Allogeneic bone marrow transplantation in multiple myeloma

A 28-year-old woman with Bence-Jones multiple myeloma (MM) presented with several osteolytic lesions and a massive bone marrow infiltration with mature plasmocytes. After 6 cycles of chemotherapy with melphalan and prednisone, the patient, in apparent clinical remission, underwent allogeneic bone marrow transplantation (BMT) from her brother. The patient has been followed up for 23 months, showing complete remission by clinical and laboratory criteria. Other cases of MM treated with BMT and reported in the literature are reviewed and discussed.     

High-dose chemoradiotherapy with syngeneic bone marrow transplantation for multiple myeloma: a case report and literature review

We had the opportunity to treat a patient with progressive heavily pretreated multiple myeloma with high-dose chemoradiotherapy with hematopoietic rescue by syngeneic bone marrow transplantation. The patient was a 53-year-old male who had previously received melphalan, prednisone, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU), vincristine, and standard radiation therapy. At the time of bone marrow transplantation, he had increasing bone pain, increasing M-protein (IgG kappa), and a bone marrow diagnostic of myeloma. The transplant regimen consisted of cyclophosphamide, 60 mg/kg intravenously for 2 days, and total body irradiation--1,200 rads given as 200-rad fractions, twice daily for three days. The transplant course was complicated by confusion, herpes simplex mucositis, fever, and two episodes of idiopathic diffuse interstitial pneumonia. Over the next 2 years the patient did well and was in immunologic and bone marrow complete remission. Unfortunately, 3 years after treatment, the myeloma relapsed with detectable M-protein. Three and one-half years after transplant, clinical relapse occurred with bone pain and lytic lesions necessitating additional radiation and chemotherapy. Salvage therapy has produced clinical improvement and the patient is alive almost 4 years from transplant and almost 7 years from diagnosis. Although intense chemoradiotherapy did not cure this patient, substantial control of a refractory tumor was observed. This case, together with other cases of intense therapy for myeloma which are reviewed in this paper, support the concept of high-dose therapy and should foster further investigation of high-dose therapy.     

Dual targeting of Bruton's tyrosine kinase and Janus kinase 3 with rationally designed inhibitors prevents graft-versus-host disease (GVHD) in a murine allogeneic bone marrow transplantation model

The purpose of the present study was to evaluate the effectiveness of targeting Bruton's tyrosine kinase (BTK) with a specific BTK inhibitor, alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13), for prevention of acute fatal graft-versus-host disease (GVHD) in a murine model of allogeneic bone marrow transplantation (BMT). Vehicle-treated control C57BL/6 mice receiving bone marrow/splenocyte grafts from allogeneic BALB/c donors developed severe multi-organ acute GVHD and died after a median survival time (MST) of 40 d. LFM-A13 treatment (25 mg/kg/d) significantly prolonged the MST of the BMT recipients to 47 d. The probability of survival at 2 months after BMT was 2 +/- 2% for vehicle-treated control mice and 22 +/- 6% for mice treated with LFM-A13 (P = 0.0008). Notably, the combination regimen of LFM-A13 plus the standard anti-GVHD drug methotrexate (MTX) (10 mg/m(2)/d) was more effective than LFM-A13 alone, while the combination regimen of LFM-A13 plus the novel anti-GVHD drug JANEX-1 (60 mg/kg/d), targeting Janus kinase 3, was more effective than LFM-A13, JANEX-1 or MTX alone. More than 70% of recipients receiving this most effective GVHD prophylaxis (LFM-A13 + JANEX-1) remained alive throughout the 80-d observation period with an MST of >80 d. Taken together, these results indicate that targeting BTK with the chemical inhibitor LFM-A13 may attenuate the severity of GVHD, especially when it is combined with other anti-GVHD drugs, such as MTX and JANEX-1.     

Thiotepa, busulfan, and cyclophosphamide: a new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma

Forty patients with multiple myeloma received thiotepa (750 mg/m2), busulfan (10 mg/kg), and cyclophosphamide (120 mg/kg) (TBC) followed by autologous bone marrow or blood stem cell support. Granulocyte-Colony stimulating factor (G-CSF) was administered to accelerate hematopoietic recovery. Sixty-five percent of all patients responded to this treatment. Eighty-eight percent of patients transplanted in partial remission had a further reduction of the myeloma and 53% achieved a complete remission. Forty-eight percent of patients with refractory myeloma responded. All responding patients transplanted during partial remission or with primary refractory myeloma remain free of progression for a period of 4 to 24 months post-transplant, but the remission duration of patients treated in refractory relapse was short (4 months). Five of 24 patients transplanted with marrow and none of 16 receiving blood stem cells died of treatment-related complications. Use of blood stem cells resulted in more rapid granulocyte and platelet recovery. We conclude that TBC is an effective, relatively well tolerated, preparative regimen for patients with multiple myeloma.     

Allogeneic bone marrow transplantation in multiple myeloma: a report of four cases

Allogeneic bone marrow transplantation offers a new and promising form for treatment of multiple myeloma incurable with chemotherapy. We present four cases of advanced multiple myeloma given bone marrow transplantation from HLA-identical and MLC-negative sibling donors. One patient had a recurrent plasmacytoma 8 months later and one died 12 days after the transplantation whereas the other two are in good clinical remission 15 and 19 months post-transplantation.     

Prevention of diabetes in nonobese diabetic mice by nonmyeloablative allogeneic bone marrow transplantation

OBJECTIVE: Autoimmune diabetes in nonobese diabetic (NOD) mice can be prevented by allogeneic bone marrow transplantation (BMT) from diabetes-resistant murine strains. Donor-specific tolerance can also be induced by BMT; however, clinical application of nonmyeloablative conditioning prior to BMT may be essential for reducing transplant-related toxicity and mortality. In this study, we have attempted to treat autoimmunity using a new nonmyeloablative regimen for BMT. MATERIALS AND METHODS: Na?ve NOD were irradiated with 650 cGy and injected intravenously (i.v.) with splenocytes from overtly diabetic NOD mice for induction of diabetes mellitus. Three days later, experimental mice received allogeneic C57BL/6 or (C57BL/6 x BALB/c) F1 bone marrow (BM) cells i.v. for intentional activation of donor-reactive cells, and 24 hours later intraperitoneal injection of cyclophosphamide (CY) for selective depletion of alloreactive cells. In order to induce chimerism, recipients were given a second IV inoculum of donor BM 1 day after CY. RESULTS: Our method of nonmyeloablative BMT converted recipients to full or to mixed chimeras and prevented development of diabetes. Although NOD mice treated with 200 mg/kg CY died of graft-vs-host disease (GVHD), we observed diabetes-free survival for >300 days in 90% of C57BL/6 --> NOD BM chimeras treated with 60 mg/kg CY. CONCLUSION: Our data show that allogeneic BMT after reduced-intensity conditioning based on deletion of activated donor-reactive host cells by means low-dose CY results in prevention of autoimmune diabetes by converting recipients to stable, GVHD-free BM chimeras.     

Long-term follow-up of leukaemia patients after related cryopreserved allogeneic bone marrow transplantation

We have previously shown that allogeneic bone marrow transplantation (BMT) with cryopreserved donor marrow cells can be used without prolonging the engraftment time or interfering with the reconstitution of haemopoiesis. In this report we extend our initial observations of the first 40 patients who underwent allogeneic bone marrow transplantation from related donors with cryopreserved donor bone marrow for haematological malignancies, including the long-term follow-up data of the previously reported patients. The outcome of these patients was compared with that of 40 related BMT recipients receiving fresh donor bone marrow (historic control group). Time until engraftment of all patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0.5 × 10⁹/l 17 d (range 11–24 d) versus 17.5 d (range 10–28 d); platelets > 20 × 10⁹/l 21 d (range 11–85 d) versus 22 d (range 13–69 d), respectively). There was the same incidence of acute and chronic GvHD in patients receiving either cryopreserved bone marrow or fresh bone marrow (acute GvHD ≥ II 61% v 60% and chronic GvHD 56% v 52%, respectively). Chimaerism studies showed no difference between the patient groups. Furthermore, the two groups did not differ in day 100 survival (82% v 72%). With a median follow-up of 520 d (range 47–1365 d) and 1289 d (range 48–1849 d), 60% of the patients receiving cryopreserved and 53% of the patients receiving fresh allogeneic donor bone marrow, respectively, are alive. We conclude that cryopreservation of allogeneic related donor bone marrow does not adversely affect engraftment, does not decrease the incidence of severe acute GvHD, and does not seem to affect the day 100 survival or long-term haemopoiesis.     

Plasmodium falciparum causing hemophagocytic syndrome after allogeneic blood stem cell transplantation

We describe a case of Plasmodium falciparum infection in a 25-year-old male patient with a myelodysplastic syndrome, who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) in September 2003. Conditioning regimen consisted of total body irradiation (10 Gy) and cyclophosphamide 60 mg/kg for 2 days. A dose of 4 x 10(6) CD34+ cells/kg was transfused. Engraftment was well documented on day 17 post-transplantation. Spiking fevers occurred on days 19 and 21, associated with a pancytopenia, hepatosplenomegaly and neurological signs. P. falciparum parasites were found on the peripheral blood smear (parasitemia = 23%). Marrow aspiration showed P. falciparum parasites and proliferation of mature histiocytes with hemophagocytosis. Quinine 10 mg/kg i.v. three times a day for 10 consecutive days was given. The fever subsided within 3 days, and pancytopenia vanished in 14 days. Parasitemia cleared in 6 days. The patient left the unit on day 46 with no further complications. The screening of donors showed that infection was acquired from two blood units (from a single donor) given 5 days before transplantation. We report the first case of profound hemophagocytosis in immunosuppressed patient with malaria of high parasitemia after a bone marrow transplant.     

High-dose cytostatic agents in allogeneic bone marrow transplantation: comparison of the engraftment promoting potential

We investigated the potential of various cytostatic agents for preventing graft rejection following allogeneic bone marrow transplantation. LEW rats received a lethal dose (35 mg/kg) of busulfan followed by injection of 1 x 10(8) F1(CAP x LEW) marrow cells, which are unable to induce a graft-versus-host reaction in LEW recipients. Rejection of the marrow graft was assessed by monitoring haematocrit and granulocyte counts. Due to its weak immunosuppressive activity, busulfan by itself is unable to allow engraftment of allogeneic marrow. Therefore, agents administered in addition to busulfan can be tested for their capacity to prevent marrow graft rejection. 120 mg/kg of cyclophosphamide, 20 mg/kg of ACNU and 240 mg/kg of ifosfamide completely prevented rejection of the allogeneic marrow. Maximum doses of BCNU applicable in conjunction with busulfan reduced the rejection rate to 12% (30 mg/kg) and 17% (40 mg/kg), whereas the antitumour agents thiotepa, melphalan, and carboplatin exhibited a very limited engraftment-promoting potential in this experimental setting. Thus, BCNU (carmustine), ACNU (nimustine), and ifosfamide might be suitable candidates for conditioning of allogeneic bone marrow graft recipients.     

Comparison of cyclophosphamide, cytarabine, and etoposide as immunosuppressive agents before allogeneic bone marrow transplantation

Etoposide and cytarabine have been shown to exert high antileukemic activity and are currently under study as preparatory agents before allogeneic bone marrow transplantation. However, data concerning their engraftment-promoting potency are scarce. Therefore, we tested these agents in LEW rats receiving a myeloablative dose of busulfan followed by transfer of F1 (CAP X LEW) marrow, which is unable to induce a graft- v-host reaction (GVHR). Since busulfan by itself has only minor immunosuppressive potency, graft rejection ensues unless etoposide, cytarabine, or cyclophosphamide provide additional immunosuppression to facilitate durable engraftment. Before allogeneic bone marrow transplantation in humans, 120 mg/kg of cyclophosphamide, 60 mg/kg of etoposide, or 900 mg/kg of cytarabine are the standard doses given in conjunction with total body irradiation. Seventy-five percent of these doses administered in addition to busulfan resulted in rejection rates of 75% for cytarabine and 58% for etoposide, respectively, whereas no rejections were observed with cyclophosphamide. These data indicate that etoposide and cytarabine are inferior to cyclophosphamide in their rejection-preventing potential. Using either of these agents as substitutes for cyclophosphamide before allogeneic bone marrow transplantation may increase the risk of graft rejection in HLA- mismatched bone marrow transplantation and, in case of HLA identity, if T-depleted marrow is administered.     

Allogeneic bone marrow transplantation following busulfan-cyclophosphamide with or without etoposide conditioning regimen for patients with acute lymphoblastic leukaemia

Summary We have investigated the feasibility and efficacy of administering a radiation-free preparative regimen in the setting of allogeneic bone marrow transplantation (BMT) in 40 consecutive patients with acute lymphoblastic leukaemia (ALL). Busulfan (4 mg/kg/d × 4 d) and cyclophosphamide (50 mg/kg/d × 4 d) (BuCy4) were given in 29 patients and 11 received busulfan (4 mg/kg/d × 4 d), etoposide (60 mg/kg) and cyclophosphamide (60 mg/kg/d × 2 d) (BuCy + VP-16). Median age was 22 years (range 1–50); 11 patients were children ≤ 15 years of age. All children and 20 adults were at high risk of relapse pretransplant. Nine adults and one child died from transplant-related toxicity. 11 patients relapsed at a median of 11 months post-transplant (range 2–27). The 3-year Kaplan-Meier estimated probability of relapse was 42.1% and found to he significantly lower in patients with chronic GVHD (P=0.03). 19 patients are leukaemia-free survivors with a median follow-up of 33 months (range 7–59). The Kaplan-Meier actuarial probability of disease-free survival at 3 years was 43% for all patients, 63.6% for children versus 30.2% for adults (P = 0.24) and 51.6% for patients transplanted in first remission versus 30.2% for those transplanted in subsequent remissions (P = 0.20).     

Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma

Summary. This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m²) and etoposide (900 mg/m²) with GM-CSF. During haematological recovery, at least 2 × 10⁶ CD34⁺ mononuclear cells/kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m²), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to >1.0 × 10⁹/1 after a median of 10 d and of platelets to 50 × 10⁹/1 after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34⁺ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.     

Donor cell-derived acute lymphocytic leukemia after allogeneic stem cell transplantation for multiple myeloma

Donor cell leukemia (DCL) is a rare, but well-known, complication after allogeneic hematopoietic cell transplantation. We report a case of donor cell-derived acute lymphocytic leukemia (ALL) occurring in a 55-year-old man after allogeneic bone marrow transplantation (allo-BMT) from an HLA-matched unrelated donor for refractory multiple myeloma (MM). Molecular analysis using short tandem repeat sequences proved the ALL to be of donor origin. He underwent combination chemotherapy and second allo-BMT from an alternative donor. After second allo-BMT, extramedullary myeloma relapsed as tumor, but was successfully treated with proteasome inhibitor, bortezomib. However, he died from severe graft-versus-host disease four months after the second transplantation. Although more than 50 cases of DCL have been reported, there have been only two reports of DCL developed in MM patients including our case. This rare complication may give some insights into leukemogenesis.     

Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma

We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM.