Human urinary macrophage colony-stimulating factor reduces the incidence and duration of febrile neutropenia and shortens the period required to finish three courses of intensive consolidation therapy in acute myeloid leukemia: a double-blind controlled study.

PURPOSE: To determine whether macrophage colony-stimulating factor (M-CSF) reduces the incidence and duration of febrile neutropenia during three courses of intensive consolidation therapy and whether it shortens time to complete consolidation therapy. PATIENTS AND METHODS: In 198 adult patients with acute myeloid leukemia (AML) in complete remission (CR), M-CSF (8 x 10(6) U/d) or placebo was administered from 1 day after the end of each consolidation chemotherapy for 14 days. RESULTS: The duration and incidence of febrile neutropenia was significantly reduced by 34% (P = .00285) and 17% (P = .02065), respectively, in 88 assessable patients in the M-CSF group compared with those in 94 assessable patients in the placebo group. Patients in the M-CSF group had 565 days and 133 episodes of febrile neutropenia during 7,901 days at risk, while patients in the placebo group had 977 days and 185 episodes during 9,077 days at risk. The median period required to finish the three courses of consolidation therapy was 93 days in the M-CSF group, which was significantly shorter than 110 days in placebo group (P = .0050). In the M-CSF group, the recovery of neutrophils and platelets was significantly faster (P = .0348 and P = 0.0364, respectively), the administration of systemic antimicrobial agents tended to be less (P = .0839), and the frequency of platelet transfusion (P = .0259) and the total volume of transfused platelets (P = .0292) were significantly less. However, there was no significant difference in the disease-free survival. CONCLUSION: M-CSF significantly reduced the incidence and duration of febrile neutropenia during the intensive consolidation therapy, and shortened the time to complete consolidation chemotherapy in AML.

Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group.

PURPOSE: We conducted a multicenter study of differentiation therapy with all-trans retinoic acid (ATRA) followed by intensive chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL) and analyzed the prognostic factors for predicting complete remission (CR), event-free survival (EFS), and disease-free survival (DFS). PATIENTS AND METHODS: All patients received ATRA until CR. If patients had an initial leukocyte count greater than 3.0 x 10(9)/L, they received daunorubicin (DNR) and behenoyl cytarabine (BHAC). During therapy, if patients showed blast and promyelocyte counts greater than 1.0 x 10(9)/L, they received additional DNR and BHAC. After achieving CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. RESULTS: Of 198 registered, 196 were assessable (age range, 15 to 86 years; median, 46) and 173 (88%) achieved CR. Multivariate analysis showed that no or minor purpura at diagnosis (P = .0046) and age less than 30 years (P = .0076) were favorable factors for achievement of CR. Predicted 4-year overall survival and EFS rates were 74% and 54%, respectively, and the 4-year predicted DFS rate for 173 CR patients was 62%. Multivariate analysis showed that age less than 30 years (P = .0003) and initial leukocyte count less than 10 x 10(9)/L (P = .0296) were prognostic factors for longer EFS, and initial leukocyte count less than 10.0 x 10(9)/L was a sole significant prognostic factor for longer DFS (P = .0001). CONCLUSION: Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

Clonal evolution to acute myeloblastic leukemia with MLL gene rearrangement from trisomy 8 clone.

A 20-year-old Japanese man was referred because of severe pancytopenia with 14% of abnormal blasts in hypocellular bone marrow. After treatment by granulocyte colony-stimulating factor (G-CSF) and transfusions of red blood cells, spontaneous remission was subsequently achieved. After 3 months' remission, however, the patient developed AML characterized by the abnormal karyotype: 46XY,+8,t(9;11)(p22;q23). FISH study revealed the presence of trisomy 8 clone also in the hypoplastic state. While MLL-AF9 chimeric mRNA was observed in leukemic cells, it was not detectable in bone marrow cells from the hypoplastic state by RT-PCR. This is the first report of a trisomy 8 clone which evolved into one with a MLL gene rearrangement.

Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23).

We describe two new human leukemia cell lines, MOLM-13 and MOLM-14, established from the peripheral blood of a patient at relapse of acute monocytic leukemia, FAB M5a, which had evolved from myelodysplastic syndrome (MDS). Both cell lines express monocyte-specific esterase (MSE) and MLL-AF9 fusion mRNA. Gene fusion is associated with a minute chromosomal insertion, ins(11;9)(q23;p22p23). MOLM-13 and MOLM-14 are the first cell lines with, and represent the third reported case of, MLL gene rearrangement arising via chromosomal insertion. Both cell lines carry trisomy 8 which was also present during the MDS phase, as well as the most frequent trisomies associated with t(9;11), ie, +6, +13, +19 variously present in different subclones. Despite having these features in common, differences in antigen expression were noted between the two cell lines: that of MOLM-13 being CD34+, CD13-, CD14-, CD15+, CD33+; whereas MOLM-14 was CD4+, CD13+, CD14+, CD15+, CD33+. Differentiation to macrophage-like morphology could be induced in both cell lines after stimulation with INF-gamma alone, or in combination with TNF-alpha, which treatment also induced or upregulated, expression of certain myelomonocyte-associated antigens, including CD13, CD14, CD15, CD64, CD65 and CD87. Together, these data confirm that both cell lines are likely to be novel in vitro models for studying monocytic differentiation and leukemogenesis.

Low-dose melphalan for treatment of high-risk myelodysplastic syndromes.

Twenty-one consecutive patients with high-risk myelodysplastic syndromes (MDS) including six with refractory anemia with excess blasts (RAEB) and 15 with RAEB in transformation (RAEBt) were treated with daily oral low-dose melphalan (2 mg/day). Seven patients achieved complete remission (CR), one patient partial response, and four minor response while the remaining eight did not respond. The median age of the patients was 65 (range 56-83 years). The mean total amount of melphalan given was 140+/-19 mg in patients who achieved CR. The median duration of CR was 14.5 months. Serious toxicity was not encountered in any of the cases. Neither marrow suppression nor pancytopenia was observed during the administration of melphalan in patients who achieved CR. The clinical features of CR patients included normal karyotype and hypocellular marrow in biopsied specimen from the lilac bone. These observations suggest that melphalan may exert some differentiation effects on leukemic cells in addition to cytotoxic effects. Our study indicates that daily administration of low-dose melphalan is worth trying in the treatment of elderly patients with high-risk MDS.

Characterization of FDCP-2, a cloned hemopoietic progenitor cell deficient in homing protein.

The progenitor cell clone, FDCP-2, was found to lack the expression of membrane homing lectin that recognizes galactosyl and mannosyl residues of glycoconjugate on the surface of hemopoietic stroma. Adherence of these cells to hemopoietic stroma is significantly less than that of either normal clones B6SUt or FDCP-1, although their adherence to nonhemopoietic stroma 3T3 is preserved. As determined by electron microscopy, the cells lack microvilli, which in their normal counterparts serve to mediate the contact and adherence to hemopoietic stroma. This cell line can be useful as a negative control in elucidating the molecular basis of the homing phenomenon and its function in the regulation of hemopoiesis.

G-CSF reduces IFN-gamma and IL-4 production by T cells after allogeneic stimulation by indirectly modulating monocyte function.

Despite a 10-fold increase of T cell dose, the incidence and severity of acute GVHD following allogeneic transplantation of G-CSF-mobilized PBSC is not increased compared to BMT. Experimental murine studies demonstrate that G-CSF polarizes donor T cells toward a type 2 cytokine response. To determine whether G-CSF alters T cell cytokine responses, we investigated the effects of G-CSF administration on T cell proliferative and cytokine responses to alloantigen and Con A in nonadherent PBMC (NAC) and CD3+ T cells obtained from normal individuals before and after G-CSF administration (10 microg/kg x 4 days). Although T cell proliferative and cytokine (IFN-gamma and IL-4) responses to alloantigen stimulation and Con A were significantly reduced in post-G-CSF NAC, they were restored by the removal of non-T cells from post-G-CSF NAC. Furthermore, there was less T cell alloreactivity in MLR in the presence of autologous post-G-CSF monocytes than in the presence of pre-G-CSF monocytes. This alteration was not replicated in vitro by culturing PBMC with G-CSF. These results suggest that G-CSF administration suppresses T cell proliferative and cytokine (IFN-gamma and IL-4) responses to allogeneic stimulation by indirectly modulating monocyte function. Bone Marrow Transplantation (2000).

Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation.

CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical entity which is the prototype of the putative NK cell lymphomas. A 16-year-old Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose chemotherapy supported with syngeneic peripheral blood stem cell transplantation (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional chemotherapy before transplantation, resulting in a partial response. PBSC were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She achieved complete remission and is now surviving in continuous complete remission for more than 30 months after syngeneic PBSCT. Thus, marrow-ablative chemotherapy facilitated by autologous or allogeneic PBSCT should be considered as part of the primary therapy for poor prognosis NK cell lymphomas.

The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood stem cells.

A simplified method for cryopreservation at -80 degrees C of peripheral blood stem cells (PBSC) has been increasingly used for autologous PBSC transplantation in Japan. Although this method, using 6% hydroxyethyl starch (HES) and 5% dimethyl sulfoxide (DMSO) as a cryoprotectant without rate-controlled freezing, has several advantages over the conventional method using 10% DMSO with rate-controlled freezing, little is known about effects of long-term cryopreservation for years and thawing process on hematopoietic progenitors. We examined the recovery rates of BFU-E and CFU-GM in sample tubes cryopreserved by the simplified method under various conditions as follows: (1) long-term storage for 1-5 years; (2) DMSO exposure for 1 h after rapid thawing; and (3) thawing at a lower temperature other than 37 degrees C. In our study, we found that the recovery rates of BFU-E and CFU-GM were not affected by the length of cryopreservation period; they remained at more than 70% on average for 16-61 months. In our hands, a 1-h exposure to DMSO after rapid thawing was not toxic for hematopoietic progenitors. Furthermore, there was no significant difference in the recovery rates of BFU-E and CFU-GM between thawing at 37 degrees C and 20 degrees C. These observations indicate that PBSC cryopreserved for at least 5 years by the simplified method can be used clinically without losing hematopoietic activity, and suggest that hematopoietic activity of the thawed PBSC may be unaffected when PBSC are infused slowly within 60 min or even when PBSC are thawed gradually at room temperature.

Hematopoietic progenitor cells from allogeneic bone marrow transplant donors circulate in the very early post-transplant period.

Despite the therapeutic efficacy of allogeneic bone marrow transplantation (allo-BMT), circulating hematopoietic progenitor cells after bone marrow transplantation have not been well characterized. In the present study, we focused on these 'post-transplant circulating progenitor cells (PTCPC)' which may be on their way to bone marrow. We analyzed the number of myeloid progenitor cells (CFU-GM) per 10 ml of peripheral blood (PB) on days 0 (just before transplantation), 1 (8-15 h after the completion of transplantation), 2, 3, 5, 7, 10, 14, 17, 21, 28 and 35 after allo-BMT in five transplant patients using a standard methylcellulose assay. In addition, high proliferative potential colony-forming cells (HPP-CFC) of the harvested donor bone marrow (BM) and day 1 PB of recipients were assayed in five patients. The origin of HPP-CFC from day 1 PB was analyzed by polymerase chain reaction of a DNA region containing a variable number of tandem repeats. The replating potential of these HPP-CFC was evaluated by a secondary colony assay. The proportion of CD38negative cells among CD34+ cells in the harvested BM and day 1 PB was evaluated by two-color flow cytometric analysis. The number of CFU-GM on day 1 ranged from 6 to 73/10 ml PB, and became undetectable on day 5. The reappearance of PTCPC was observed on day 14, along with hematopoietic recovery. The proportion of HPP-CFC among myeloid colonies from day 1 PB was significantly higher than that from harvested BM (44.3+/-10.4% vs 11.3+/-2.1%, respectively, n=5, P=0.0030). These HPP-CFC from day 1 PB were confirmed to be of donor origin. More than 90% of these HPP-CFC had replating potential. Two-color flow cytometric analysis revealed that the proportion of CD34+CD38negative cells was significantly higher in day 1 PB than in the harvested BM (61.0+/-16.5% vs 9.3+/-3.5%, respectively, n=7, P=0.0002). These observations suggest that both primitive and committed transplanted myeloid progenitor cells may circulate in the very early period following allo-BMT.

Androgen therapy in combination with granulocyte colony-stimulating factor and erythropoietin in a patient with refractory anemia.

Initial treatment with androgen (metenolone acetate) alone for 19 weeks had no effect in a 45-year-old Japanese female with refractory anemia (RA). The patient achieved trilineage hematologic recovery after addition of recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (Epo) to the androgen therapy. Anemia progressed after the cessation of metanolone acetate, but was effectively treated by the readministration of metenolone acetate. Thus, the androgen therapy in combination with hematopoietic growth factors such as G-CSF and/or Epo may be effective in patients with RA.

Replating potential of colony-forming units of granulocytes/macrophages (CFU-GM) expanded ex vivo by stem cell factor, interleukin (IL)-3, IL-6, granulocyte colony-stimulating factor, erythropoietin with or without thrombopoietin.

Ex vivo expansion systems of hematopoietic progenitor cells (HPC) have been extensively studied and their clinical application is under investigation. However, it is not known whether HPC expanded ex vivo will be able to retain their replating potential. CD34+ cells isolated from cord blood were cultured in Iscove's modified Dulbecco's medium supplemented with 10% fetal bovine serum, 1.0% bovine serum albumin, 50 ng/ml stem cell factor, 50 ng/ml interleukin-3 (IL-3), 50 ng/ml IL-6, 100 ng/ml granulocyte colony-stimulating factor, and 3 U/ml erythropoietin for 0, 5, 7, 10, 14, and 21 days. After the expansion cultures, granulocyte/macrophage progenitor cells (CFU-GM) were assayed from each culture by the standard methylcellulose method. After 14 days of culture, CFU-GM-derived colonies were randomly picked up and processed for the replating assay. The fold increase of CFU-GM peaked at day 7 of the expansion culture (29.8 +/- 7.7-fold, n = 5), followed by a decline until day 21. In the replating assay of CFU-GM from freshly isolated CD34+ cells, the mean replating efficiency was 91.2 +/- 4.7%. The replating efficiency decreased gradually with the time of the expansion culture. At day 7 when the fold increase of CFU-GM reached its peak, the replating efficiency had dropped to 47.5 +/- 2.3%, followed by a further decline to 5.3 +/- 3.4% at day 21. Furthermore, the addition of 100 ng/ml thrombopoietin to this expansion system failed to prevent the decline of replating efficiency. These observations suggest that the replating potential of CFU-GM may decrease in the ex vivo expansion system, even when their fold increase reaches its peak. This should be taken into consideration when HPC expanded ex vivo are used in clinical transplantation.

Granulocyte colony-stimulating factor and lineage-independent modulation of VLA-4 expression on circulating CD34+ cells.

Although the use of allogeneic transplants of peripheral blood stem/progenitor cells (PBSCs) is increasing, the precise mechanism of PBSC mobilization has not yet been fully clarified. We examined the expression of some adhesion molecules on CD34+ cells from steady-state bone marrow (BM), granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs, and cytotoxic drugs plus G-CSF-mobilized PBSCs. Irrespective of mobilization method, very late antigen (VLA)-4 expression on circulating CD34+ cells was significantly lower than on steady-state BM CD34+ cells. To elucidate the influence of lineage commitment on VLA-4 expression of circulating CD34+ cells, we analyzed VLA-4 expression on different subsets of CD34+ cells with or without CD33, CD38, CD5, or CD10 antigens, or Glycophorin A in G-CSF-mobilized PBSCs and steady-state BM from related donors, using 3-color flow cytometry. VLA-4 on circulating CD34+ subsets was less expressed than on each corresponding subset of steady-state BM CD34+ cells. Furthermore, VLA-4 positive rates showed no significant difference among the CD34+ subsets. Finally, the data comparing CD34+ cells from steady-state and G-CSF-mobilized PBSCs revealed no differences in terms of VLA-4 expression. These data suggest that reduced expression of VLA-4 may be a result of peripheralization of CD34+ cells from bone marrow, which occurs in a G-CSF- and lineage-independent fashion.

Autoimmune hemolytic anemia in allergic granulomatous angitis (Churg-Strauss syndrome).

We describe a patient with allergic granulomatous angitis who developed autoimmune hemolytic anemia (AIHA). A 44-year-old male had been suffering from bronchial asthma. On admission, laboratory tests revealed the presence of severe eosinophilia (21,500/microliters), elevation of total immunoglobulin E (IgE), high lactic dehydrogenase (LDH) and low haptoglobin levels, in addition to moderate reticulocytosis. During admission, the patient showed almost simultaneous occurrence of vasculitis in the extremities, severe hemolysis and exacerbation of asthma in relation to the progression of eosinophilia. Both IgM and IgG autoantibodies were considered to be responsible for hemolysis. Interestingly, serum levels of interleukin-4 (IL-4) and IL-5 were increased in association with eosinophilia and increased IgE production. These findings suggest that the AIHA in this patient is mediated or enhanced at least partly by high IL-4 and IL-5 production. Although AIHA in this syndrome is very rare, it should be considered as a clinical manifestation.

Trisomy 12 and t(14;18) in B-cell chronic lymphocytic leukemia.

We report a case of B-cell chronic lymphocytic leukemia (B-CLL) in which trisomy 12 and t(14;18)(q32;q21) were simultaneously detected in the same leukemic clone. Southern blot analysis showed that the BCL2/IgJH rearrangement occurred at the major breakpoint region in the hot spot of the BCL2 gene. Double color fluorescence in situ hybridization analysis using multiple probes indicated that clonal B-cell with t(14;18) represented a subpopulation of the total leukemic cells and that trisomy 12 followed t(14;18) as the cytogenetic aberration in the development of B-CLL. Our findings suggests that both the t(14;18) and the trisomy are secondary chromosomal changes in the leukemogenesis of B-CLL.

Graft rejection and recovery of host-derived hematopoiesis after allogeneic bone marrow transplantation: relation to conditioning with high dose etoposide and total body irradiation.

Engraftment failure following allogeneic bone marrow transplantation (BMT) is rare in patients with acute leukemia, after frequent conditioning with marrow-lethal chemoradiotherapy. We evaluated the efficacy of a preparatory regimen consisting of fractionated total body irradiation (TBI) (12 Gy in six fractions) and high dose etoposide (60 mg/kg) administered as an 8-h infusion for allogeneic BMT in 16 consecutive patients with acute leukemia. Although 14 patients showed complete and sustained engraftment, the remaining two patients rejected bone marrow grafts from HLA-identical sibling donors and showed subsequent recovery of host-derived hematopoiesis. Despite the limited number of patients, this observation suggests that the immunosuppressive potential of etoposide may be inferior to that of cyclophosphamide (CY) and that etoposide as an alternative to CY as an antileukemic and immunosuppressive agent in allogeneic BMT may increase the risk of graft rejection.

G-CSF-induced mobilization of peripheral blood stem cells for allografting: comparative study of daily single versus divided dose of G-CSF.

We conducted a comparative study on a daily single versus a divided dose of G-CSF for G-CSF-induced mobilization of peripheral blood stem cells (PBSC) in eleven HLA-identical sibling donors of allogeneic PBSC transplantation (PBSCT). Six donors received double subcutaneous injections of G-CSF at a dose of 5 micrograms/kg x 2/day for 5 days (Group A), while the remaining five received single subcutaneous injection at a dose of 10 micrograms/kg/day for 5 days (Group B). The numbers of circulating CD34+ cells, myeloid progenitors (CFU-GM) and erythroid progenitors (BFU-E) reached peak values at day 5 of G-CSF administration in both groups. The mean number of CD34+ cells harvested per apheresis was 4.4 x 10(6)/kg (cells/body weight of each donor, range: 0.8-7.9 x 10(6)/kg) in Group A and 5.1 x 10(6)/kg (range: 3.0-9.0 x 10(6)/kg) in Group B. There were no significant differences between these two groups in total numbers of CFU-GM, BFU-E, or T-lymphocytes harvested. Adverse effects including mild to moderate bone pain and thrombocytopenia were transient and well tolerated. No difference was observed in the incidence of adverse effects between the two groups. These observations suggest that there is no difference in G-CSF-induced mobilization of PBSC between daily single and divided dose of G-CSF to collect a sufficient number of PBSC for engraftment after allo-PBSCT.

No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group.

To assess the efficacy of etoposide added to the standard remission induction therapy for acute myeloid leukemia (AML), newly diagnosed adult AML patients were randomized to receive either daunorubicin (40 mg/m2/day x 4 or more), behenoyl cytarabine (200 mg/m2/day x 10 or more), and 6-mercaptopurine (70 mg/m2/day x 10 or more) (BHAC-DM), or the same three drugs plus etoposide (100 mg/m2/day x 5) (BHAC-EDM) for response-oriented individualized induction therapy. The patients achieving complete remission (CR) received the same 3 courses of consolidation therapy followed by 6 courses of maintenance/intensification therapy. M3 patients were excluded because all-trans retinoic acid was used. Of 667 patients registered, 655 were evaluable. The median age was 49 (range 15 to 85). CR rates were 77% in the BHAC-DM group and 75% in the BHAC-EDM group. In 173 M4 patients, CR rates were 86% and 69% (P = 0.009), and in 32 M5 patients, 80% and 77% (P = 0.810) in the BHAC-DM and the BHAC-EDM groups, respectively. The predicted 6-year overall survival rates were 30% and 38% (P = 0.925) for the BHAC-DM and BHAC-EDM groups, and the disease-free survival rates of CR patients were 25% and 35% (P = 0.352), respectively. Nonhematological toxicities after the first course of induction therapy were almost equal among the two groups, with the exception of a greater loss of hair (P = 0.024) and more frequent diarrhea (P = 0.013) in the BHAC-EDM group. We concluded that in the present study, the addition of etoposide to the standard individualized induction therapy showed no advantage in adult AML, even among M4 and M5 patients.

All-trans retinoic acid therapy for newly diagnosed acute promyelocytic leukemia: comparison with intensive chemotherapy. The Japan Adult Leukemia Study Group (JALSG).

We analyzed the results of treating patients with newly diagnosed acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in the JALSG AML-92 study and compared them with those of the AML-87 and AML-89 studies, which consisted of standard chemotherapy. In the AML-92 study, patients were scheduled to receive 45 mg/ m2 oral ATRA daily until achievement of a complete remission (CR). If patients had initial leukocyte counts of > 3.0 x 10(9)/l, they received 40 mg/m2 daunorubicin (DNR) for 3 days and 200 mg/m2 behenoyl cytarabine (BHAC) for 5 days in addition to ATRA. During remission induction therapy, if the patients showed peripheral blood myeloblast and promyelocyte counts of > 1.0 x 10(9)/l, they received additional DNR and BHAC on the same schedule. After achievement of a CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. Of 196 evaluable patients, 173 (88%) achieved a CR: 59 of 62 (95%) treated with ATRA alone, 41 of 49 (84%) treated with ATRA plus later chemotherapy, 63 of 73 (86%) treated with ATRA plus initial chemotherapy, and 10 of 12 (83%) treated with ATRA plus both initial and later chemotherapy. The CR rate in AML-92 was significantly higher than that in AML-89, but not than that achieved in AML-87. In addition, the early mortality and relapse rates in AML-92 were significantly lower than those in AML-89, but were not than those in AML-87. At a median follow-up of 36 months the predicted 4-year event-free survival (EFS) rate for 196 evaluable patients and the 4-year disease-free survival (DFS) rate for the CR cases were 54% and 62%, respectively. There was a significant difference in DFS between AML-92 and AML-87 (P = 0.0418) but not between AML-92 and AML-89 (P = 0.0687). In contrast, significant differences in EFS between AML-92 and both AML-87 (P = 0.0129) and AML-89 (P = 0.005) were observed. These results suggest that non-cross-resistant therapy combined with ATRA and intensive chemotherapy for APL contributes synergistically to the significant improvement in EFS.

Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG).

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.