Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As 2O3, and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RAR␣ (promyelocytic leukemia-retinoic acid receptor ␣) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (>90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RAR␣ transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As2O3 mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8 -30 months (median: 18 months). Synergism of ATRA and As2O3 on apoptosis and degradation of PML-RAR␣ oncoprotein might provide a plausible explanation for superior efficacy of combinative therapy in clinic. In conclusion, the ATRA͞As2O3 combination for remission͞ maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival.A cute promyelocytic leukemia (APL) accounts for 10-15% of acute myeloid leukemia in which the maturation of granulocytic cells was blocked at the promyelocytic stage. It is also characterized by the t(15;17)(q22;q21) chromosome translocation generating the PML-RAR␣ (promyelocytic leukemia-retinoic acid receptor ␣) fusion gene, of which the leukemogenic role has been demonstrated by the transgenic mouse models (1). Although conventional chemotherapy such as anthracyclines and cytosine arabinoside (ara-C) succeeded in two-thirds of APL patients in obtaining complete remission, high frequency of early death mainly due to exacerbation of bleeding syndrome and low 5-year diseasefree survival (DFS) rates dwarf them to new drugs (2). Our group in the Shanghai Institute of Hematology (SIH) has long been interested in differentiation therapy of human cancers, as inspired by the Chinese philosophy that it is better to transform a bad element instead of simply getting rid of it. After the discovery in the 1970s to early 1980s showing that some leukemic cells could undergo phenotypic reversion under differentiation inducers (3, 4), we started to screen a...

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.