Long-term follow-up of efficacy and safety in elderly patients with chronic myeloid leukemia treated with intermittent low dose dasatinib therapy.

Intermittent low dose dasatinib therapy brought about a beneficial effect in elderly patients with chronic-phase chronic myeloid leukemia (CML-CP) without inducing severe adverse events (AEs). An 85-year-old male patient, who received twice-weekly, thrice-weekly, or four-times-weekly administration of 20 mg/day dasatinib after once-weekly administration, achieved a major molecular response two years after the start of dasatinib treatment and later sometimes achieved a deep molecular response, maintaining the efficacy for 11 years. The mean daily dose ranged from 5.7 mg to 11.4 mg. Furthermore, a 79-year-old male patient, who received thrice-weekly or every other day administration of 20 mg/day dasatinib after once-weekly administration, achieved a deep molecular response at four and half years after the start of dasatinib treatment. The mean daily dose is 8.6 mg. Intermittent low dose dasatinib therapy appears to be feasible in elderly patients with CML-CP. The goal of treatment in elderly patients with CML-CP appears to be different from that in younger patients, since they often suffer from serious AEs in the case of standard dose tyrosine kinase inhibitor therapy, followed by the dose reduction or cessation of treatment.

Development of progressive multifocal leukoencephalopathy after cord blood transplantation in a patient with refractory angioimmunoblastic T-cell lymphoma.

A patient undergoing cord blood transplantation for refractory angioimmunoblastic T-cell lymphoma was subsequently managed with long-term immunosuppressants for chronic graft-versus-host disease (GVHD). On day 591 post-transplant, she exhibited disorientation and cognitive dysfunction. Magnetic resonance imaging (MRI) of the brain revealed two hyperintense foci in the white matter, suggestive of progressive multifocal leukoencephalopathy (PML). However, we did not include PML in the differential diagnosis at that time. Unfortunately, she developed progressive cognitive impairment, and repeated brain MRIs showed a progression in lesion size. She was still taking immunosuppressants to control her GVHD, therefore we suspected PML. The diagnosis of PML was confirmed through the detection of a John Cunningham (JC) virus in the cerebrospinal fluid on day 640 post-transplant. This report highlights the critical need to consider PML in differential diagnoses for post-allogeneic transplant patients, especially those who exhibit progressive neurological symptoms while on prolonged immunosuppressant therapy.

Donor Lymphocyte Infusion for Relapsed Acute Leukemia or Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation: A Single-Institute Retrospective Analysis.

Objective The prognosis of the patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor, and therapeutic options are limited. In the present study, we investigated the efficacy and factors associated with the survival in patients with acute leukemia or myelodysplastic syndrome (MDS) who relapsed following allo-HSCT and were treated with donor lymphocyte infusion (DLI) in real-world practice. Patients Twenty-nine patients with acute myeloid leukemia21, acute lymphoid leukemia4 or MDS4 were enrolled. Eleven patients were diagnosed with hematological relapse, and 18 were diagnosed with molecular or cytogenetic relapse. Results The median injection number and median total number of infused CD3+ T cells were 2 and 5.0×107/kg, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) of grade ≥II at 4 months after the initiation of DLI was 31.0%. Extensive chronic graft-versus-host disease (cGVHD) occurred in 3 (10.3%) patients. The overall response rate was 51.7%, including 3 cases of hematological complete remission (CR) and 12 cases of molecular/cytogenetic CR. Cumulative relapse rates at 24 and 60 months following DLI in patients who achieved CR were 21.4% and 30.0%, respectively. The overall survival rates at 1, 2 and 3 years after DLI were 41.4%, 37.9% and 30.3%, respectively. Molecular/cytogenetic relapse, a longer interval from HSCT to relapse, and concomitant chemotherapy with 5-azacytidine (Aza) were significantly associated with a relatively long survival following DLI. Conclusion These results indicated that DLI was beneficial for patients with acute leukemia or MDS who relapsed after allo-HSCT and suggested that DLI in combination with Aza for molecular or cytogenetic relapse might result in favorable outcomes.

A case of Hodgkin lymphoma-type Richter syndrome presenting as small-intestinal perforation.

Hodgkin lymphoma type of Richter syndrome (HL-type RS) is a rare disease that arises in patients with chronic lymphocytic leukemia (CLL). HL-type RS lesions can manifest in various sites and are often accompanied by related symptoms. This is the first case report to describe diagnosis of HL-type RS after emergency surgery for gastrointestinal perforation caused by the development of a HL-type RS lesion. A 47-year-old man diagnosed with CLL three years prior began treatment with ibrutinib due to worsening anemia and splenomegaly two months prior to the emergency department presentation. Although splenomegaly improved, lymphocytopenia, anemia, and a newly arising mesenteric lymphadenopathy continued to worsen. He presented to the emergency department with abdominal pain, and subsequent surgery revealed small intestinal perforation and mesenteric lymphadenopathy with HL-type RS confirmed by histopathological examination of the resected small intestine. He subsequently received brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD), which effectively managed the HL-type RS. If CLL clinical presentation deviates from the typical course, an early tissue biopsy should be considered to evaluate for HL-type RS. Given the adoption of the A + AVD regimen as the standard treatment for Hodgkin lymphoma, further research is needed to evaluate its efficacy in HL-type RS.

Medium-dose etoposide, cyclophosphamide and total body irradiation conditioning potentiates anti-leukemia immunity in adults with acute lymphoblastic leukemia without aggravating graft-versus-host disease.

Medium-dose etoposide (ETP), cyclophosphamide (CY) and total body irradiation (TBI) is a beneficial conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in adults with acute lymphoblastic leukemia (ALL), especially with high-risk ALL, as compared with CY and TBI conditioning. ETP may enhance immunogenicity of leukemia-associated antigens through increased expression of major histocompatibility antigen complex class I, leading to cross-priming of T cells by dendritic cells and generating leukemia-specific cytotoxic T cells. Furthermore, ETP can eliminate activated effector T cells, sparing naïve and memory T cells, accompanied with depletion of regulatory T cells. These mechanisms are supposed to lead to inhibit immune escape of leukemia cells and enhance anti-leukemia immunity in addition to direct cytotoxicity of ETP, followed by an efficient eradication of leukemia cells. According to the findings of pharmacokinetics studies, spreading the administration of low-dose ETP may be more efficacious than non-spreading administration, to induce a potent anti-leukemia immunity without aggravating graft-versus-host disease and transplant-related toxicity. In the present review, I discuss the immunological aspects elicited by the addition of medium-dose ETP to the CY/TBI conditioning and the possible positioning of allo-HCT with this conditioning in adults with ALL, considering recent progress in non-HCT treatment including bispecific antibody-based therapy.

Hypothesis: can transfer of primary neoplasm-derived extracellular vesicles and mitochondria contribute to the development of donor cell-derived hematologic neoplasms after allogeneic hematopoietic cell transplantation?

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential treatment option for various neoplastic and non-neoplastic hematologic diseases. Although its efficacy is modest, a significant proportion of patients experience relapse, graft-versus-host disease, infection or impaired hematopoiesis. Among these, the most frequent cause of post-transplant mortality is relapse, whereas the development of de novo hematologic neoplasms from donor cells after allo-HCT occurs on some occasion as a rare complication. The mechanisms involved in the pathogenesis of the de novo hematologic neoplasms from donor cells are complex, and a multifactorial process contributes to the development of this complication. Recently, extracellular vesicles, particularly exosomes, and mitochondria have been shown to play crucial roles in intercellular communication through the transfer of specific constituents, such as deoxyribonucleic acids, ribonucleic acids, lipids, metabolites and cytosolic and cell-surface proteins. Here, I discuss the potential causative roles of these subcellular components in the development of de novo hematologic neoplasms from donor cells after allo-HCT, in addition to other etiologies.

Perspectives on the Use of a Medium-Dose Etoposide, Cyclophosphamide, and Total Body Irradiation Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation: The Japanese Experience from 1993 to Present.

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) is poor. Therefore, allogeneic HSCT (allo HSCT) for adults aged less than 50 years with ALL is performed with myeloablative conditioning (MAC) regimens. Among the several MAC regimens, a conditioning regimen of 120 mg/kg (60mg/kg for two days) cyclophosphamide (CY) and 12 gray fractionated (12 gray in six fractions for three days) total body irradiation (TBI) is commonly used, resulting in a long term survival rate of approximately 50% when transplanted at the first complete remission. The addition of 30 mg/kg (15 mg/kg for two days) etoposide (ETP) to the CY/TBI regimen revealed an excellent outcome (a long-term survival rate of approximately 80%) in adults with ALL, showing lower relapse and non-relapse mortality rates. It is preferable to perform allo HSCT with a medium-dose ETP/CY/TBI conditioning regimen at the first complete remission in high-risk ALL patients and at the second complete remission (in addition to the first complete remission) in standard-risk ALL patients. The ETP dose and administration schedule are important factors for reducing the relapse and non-relapse mortality rates, preserving a better outcome. The pharmacological study suggests that the prolonged administration of ETP at a reduced dose is a promising treatment.

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.

OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.

Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice.

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD.

Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD.

Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study.

Following a phase I/II study using mesenchymal stem cells (MSCs; JR-031) for steroid-refractory grade II or III acute graft-versus-host disease (aGVHD), a phase II/III study using the cells focused on steroid-refractory grade III or IV aGVHD was conducted. The number of infused MSCs and the number of MSC infusions were the same as the phase I/II study. No additional immunosuppressant was given for steroid-refractory aGVHD during the course of MSC infusions. Twenty-five patients (grade III, 22 patients and grade IV, 3 patients) were enrolled in this study. At 4 weeks after the first MSC infusions, six (24 %) and nine patients (36 %) achieved a complete response (CR) and partial response (PR), respectively. Durable CR by 24 weeks, which was the primary end-point, was obtained in 12 of 25 patients (48 %). At 52 weeks, 12 patients (48 %) treated with MSCs only (six patients) and MSCs plus additional treatments (six patients) were alive in CR. The survival was significantly better in patients showing overall response (OR; CR+PR) than in those showing no OR at 4 weeks. Adverse effects commonly associated with MSC infusions were not observed. Taken together, our two clinical trials suggest JR-031 to be effective for steroid-refractory aGVHD.

Allogeneic hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: potential benefit of medium-dose etoposide conditioning.

The outcomes of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) are unsatisfactory. Therefore, allogeneic (allo) HSCT has been applied to those patients in first complete remission (CR1), and has shown a long-term survival rate of approximately 50 %. In terms of myeloablative conditioning (MAC) regimen, higher dose of cyclophosphamide (CY) and total body irradiation (TBI) (the standard CY + TBI) has been generally applied to allo HSCT. Other MAC regimens such as busulfan-based or etoposide-based regimens have also been used. Among those, medium-dose etoposide (ETP) in addition to the standard CY + TBI conditioning regimen appears to be promising for allo HSCT in adult ALL when transplanted in ALL patients aged under 50 years in CR1 and also in CR2, showing an excellent outcome without increasing relapse or transplant-related mortality (TRM) rates. By contrast, reduced-intensity conditioning (RIC) regimens have also been applied to adult ALL patients and favorable outcomes have been obtained; however, relapse and TRM rates remain high. Therefore, an allo HSCT conditioning regimen which deserves further study for adult ALL patients aged under 50 years in CR1 and CR2 appears to be medium-dose ETP + CY + TBI and RIC is suitable for patients aged over 50 years or for younger patients with comorbid conditions. On the contrary, new therapeutic strategies for adult ALL patients are increasingly utilized with better outcomes; namely, various tyrosine kinase inhibitors for Philadelphia chromosome (Ph)-positive ALL, human leukocyte antigen-haploidentical HSCT, and pediatric-inspired regimens for Ph-negative ALL. Therefore, the optimal treatment modality should be selected considering patient's age, Ph-positivity, donor availability, risk classification, efficacy, and safety.

[Serum ALP elevation early after treatment is a predictor for response in myeloma patients treated with bortezomib].

Several studies have shown the predictive value of elevated serum alkaline phosphatase (ALP) level in multiple myeloma (MM) patients treated with bortezomib (BTZ). We assessed the relationship between changes in ALP levels during treatment and response. Thirty patients treated with BTZ in our hospital were analyzed retrospectively. Of the patients analyzed, 12 were male, median age was 62 years (42-86), and 11 had a history of prior chemotherapy. Eighteen patients were treated with BTZ alone or in combination with dexamethasone, while the others were treated with a combination regimen employing an alkylating agent. Seven patients had undergone autologous stem cell transplantation following BTZ therapy. Ten of 28 patients showed ALP elevation of 25% or more from the baseline at 3 weeks, and 14 of the 28 had this finding at 6 weeks. Four of 5 patients who had achieved VGPR or more showed ALP elevation of 25% or more at 3 weeks, and all five had this finding by 6 weeks. No patient without ALP elevation achieved VGPR or a better response. ALP elevation exceeding 25% from the baseline by day 42 is significantly associated with a treatment response better than VGPR (p=0.019). In conclusion, ALP elevation during BTZ treatment is a valuable prognostic marker.

A Safety and Efficacy Study of Medium-Dose Etoposide, Cyclophosphamide and Total Body Irradiation Conditioning Before Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia.

UNLABELLED: Prognosis for adult patients with acute lymphoblastic leukemia (ALL) has been reported to be approximately 35% to 50%, even after allogeneic stem cell transplantation (allo-SCT). We previously reported retrospective analyses of a conditioning regimen of medium-dose etoposide, cyclophosphamide (CY), and total body irradiation (TBI) before allo-SCT for ALL. To prospectively analyze the efficacy of this conditioning regimen, we conducted a trial prospectively. METHODS: The eligibility criteria of this study were as follows: diagnosis of ALL, aged between 15 and 50 years, in complete remission, and first SCT from HLA serologically matched donor. The primary endpoint of this study was event-free survival at 1 year after SCT, and the events were defined as death and relapse. RESULTS: Fifty eligible patients were treated, and the median age of the patients was 33.5 years. Nineteen patients were Philadelphia chromosome-positive, and 47 were in first complete remission at SCT. All patients achieved neutrophil engraftment. Grade 3 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease developed in 4 patients and 18 patients, respectively. No patient died within 100 days after SCT. One-year event-free survival was 76.0%, and 1-year overall survival was 80.0%. The cumulative incidences of relapse and non-relapse mortality at 1-year after SCT were 10.0% and 14.0%, respectively. CONCLUSIONS: Medium-dose etoposide + CY + TBI is an effective conditioning before allo-SCT for adult patients with ALL, enabling good disease control without an increase in nonrelapse mortality. A phase 3 trial comparing this regimen with the standard CY + TBI regimen for adult patients with ALL is warranted.