Central nervous system mucormycosis in a patient with hematological malignancy: A case report and review of the literature.

Invasive mucormycosis is a refractory fungal infection. Central nervous system (CNS) mucormycosis is a rare complication caused by infiltration from the paranasal sinuses or hematogenous dissemination. Here, we present a case of a brain abscess, due to mucormycosis, diagnosed using burr craniotomy. A 25-year-old Japanese woman with relapsed-refractory acute lymphoblastic leukemia underwent cord blood transplantation (CBT). The patient experienced prolonged and profound neutropenia, and oral voriconazole was administered as primary antifungal prophylaxis. The patient received a conditioning regimen on day -11 and complained of aphasia and right hemiparesis on day -6. Magnetic resonance imaging (MRI) revealed a T2-weighted high-intensity area in the left frontal cortex. A brain abscess was suspected, and liposomal amphotericin B (L-AMB) administration was started. The patient underwent CBT as scheduled and underwent neutrophil engraftment on day 14. Although the patient achieved complete remission on day 28, her consciousness level gradually deteriorated. MRI revealed an enlarged brain lesion with a midline shift sign, suggesting brain herniation. Craniotomy was performed to relieve intracranial pressure and drain the abscess on day 38, and a diagnosis of cerebral mucormycosis was confirmed. The L-AMB dose was increased to 10 mg/kg on day 43. Although the patient's consciousness level improved, she died of hemorrhagic cystitis and aspiration pneumonia. Cerebral mucormycosis should be suspected if neurological symptoms are observed in stem cell transplant recipients. Prompt commencement of antifungal therapy and debridement are crucial because mucormycosis has a poor prognosis.

Geriatric nutritional risk index as a useful prognostic factor in second allogeneic hematopoietic stem cell transplantation.

Second allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a low survival outcome and a high non-relapse mortality (NRM) rate which is a major obstacle to this treatment. We hypothesized that the status of malnourishment after first allo-HSCT as represented by the geriatric nutritional risk index (GNRI) could be used as a prognostic factor to determine the outcomes of second allo-HSCT. A total of 108 patients with a median age of 42 (range, 17-69) years, who received second allo-HSCT for disease recurrence after first allo-HSCT from our institution, were included in this study. Low GNRI had a significant impact on NRM at 2 years after second allo-HSCT: 56.9% in patients with GNRI ≤ 92 compared with 27.5% in patients with GNRI > 92 (P = 0.002). In multivariate analysis, GNRI of ≤ 92 was the only significant factor for NRM (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.15-4.56, P = 0.018). High-risk disease status at second allo-HSCT (HR 2.74, 95% CI 1.46-5.14, P = 0.002) and GNRI of ≤ 92 (HR 1.70, 95% CI 1.02-2.82, P = 0.042) were identified as significant factors for overall survival (OS). A score of 1 was assigned to each factor, and the OS rate at 2 years after second allo-HSCT decreased according to the score: 53.0% in patients with score 0, 32.3% with score 1, and 2.5% with score 2 (P < 0.001). In conclusion, GNRI could be a useful predictor for the outcomes of second allo-HSCT. A prospective study in other cohorts is warranted to validate the findings of our study.

Bone turnover markers as an aid to monitor osteoporosis following allogeneic hematopoietic stem cell transplantation.

Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (n = 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (n = 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%; p < 0.01), the mean percentage changes in BMD at the lumbar spine (- 2.9 vs. - 3.1%; p = 0.44) and femoral neck (- 3.2 vs. - 4.1%; p = 1.00), TRACP-5b levels (- 4.8 vs. 9.9%; p = 0.45), and BAP levels (6.9 vs. 1.0%; p = 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (p = 0.03, r = 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.

Unmanipulated haploidentical hematopoietic stem cell transplantation using very low-dose antithymocyte globulin and methylprednisolone in adults with relapsed/refractory acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2-2.5 mg/kg) and methylprednisolone (mPSL, 1 mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P < 0.001) and having undergone multiple HSCT (26.1% vs. 11.1%, P = 0.045). However, we found no significant differences in the 1-year overall survival (OS, 31.7% vs. 29.1%; P = 0.25), disease-free survival (DFS, 20.5% vs. 23.7%; P = 0.23), cumulative incidence of relapse (CIR, 40.0% vs. 42.8%; P = 0.92), non-relapse mortality (NRM, 39.5% vs. 33.5%; P = 0.22), or 100-day grade II-IV acute graft-versus-host disease (32.6% vs. 34.7%; P = 0.64) following HID-HSCT vs. non-HID-HSCT, respectively. Subgroup analysis stratified by disease and intensity of conditioning regimen demonstrated the same results between HID-HSCT and non-HID-HSCT. Furthermore, multivariate analysis showed that HID-HSCT was not an independent prognostic factor for OS (hazard ratio (HR) = 0.95 [95% confidence interval (CI), 0.58-1.58]), DFS (HR = 1.05 [95%CI, 0.67-1.68]), CIR (HR = 0.84 [95%CI, 0.48-1.47]), or NRM (HR = 1.28 [95%CI, 0.66-2.46]). In summary, transplant outcomes for RRAL were comparable in the HID-HSCT and non-HID-HSCT groups. HID-HSCT using very low-dose ATG and mPSL for RRAL may be a viable alternative to non-HID-HSCT.

Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies.

Polycomb repressive complexes (PRCs) are epigenetic regulators that mediate repressive histone modifications. PRCs play a pivotal role in the maintenance of hematopoietic stem cells through repression of target genes involved in cell proliferation and differentiation. Next-generation sequencing technologies have revealed that various hematologic malignancies harbor mutations in PRC2 genes, such as EZH2, EED, and SUZ12, and PRC1.1 genes, such as BCOR and BCORL1. Except for the activating EZH2 mutations detected in lymphoma, most of these mutations compromise PRC function and are frequently associated with resistance to chemotherapeutic agents and poor prognosis. Recent studies have shown that mutations in PRC genes are druggable targets. Several PRC2 inhibitors, including EZH2-specific inhibitors and EZH1 and EZH2 dual inhibitors have shown therapeutic efficacy for tumors with and without activating EZH2 mutations. Moreover, EZH2 loss-of-function mutations appear to be attractive therapeutic targets for implementing the concept of synthetic lethality. Further understanding of the epigenetic dysregulation associated with PRCs in hematological malignancies should improve treatment outcomes.

[Vacuolar myelopathy after allogeneic bone marrow transplantation in a patient with acute lymphoblastic leukemia].

Vacuolar myelopathy (VM) is known to be a neurological complication in patients with acquired immunodeficiency syndrome (AIDS). In autopsy-based studies, VM was reported in approximately 20-50% of patients with AIDS. It manifests in various says, mainly presenting as a painless spastic paraparesis with a sensory ataxia. We present a rare case of VM after bone marrow transplantation (BMT) in a patient without AIDS. A 50-year-old man developed weakness in the lower legs, leg muscle atrophy, and difficulty in walking 86 days after BMT. The patient died from septic shock on day 309. The autopsy revealed intralamellar vacuolation in the spinal white matter, which was compatible with VM.

[Tyrosine kinase inhibitor maintenance therapy following allogenic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia].

There have been many reports regarding tyrosine kinase inhibitor (TKI) administration to prevent relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, there are no commonly accepted standards for the choice of TKIs. We retrospectively analyzed the clinical features of Ph+ALL patients who received TKIs after allo-HSCT at our institution. The prophylactic administration of TKIs (pro) occurred in eight patients, and six patients received preemptive TKI administration (pre). The median follow-up period after allo-HSCT was 1,427 (range, 161-2,428) days in the pro group and 773.5 (range, 156-2,243) days in the pre group. Only one patient with non-hematological complete remission before allo-HSCT relapsed among the patients in the pro group. In the pre group, four patients treated with only TKIs achieved negativity of minimal residual disease. The 2-year overall survival rate after allo-HSCT was 85.7% in the pro group and 100% in the pre group. We used lower doses of TKIs compared with previous reports and this analysis shows that the dose is safe and effective as the treatment.

Reassessment of clinical implication of pretransplant surgical procedures for pulmonary invasive fungal lesions.

Dealing with the recent series of allogeneic hematopoietic stem cell transplantation (allo-SCT) performed this decade, we reassessed the clinical impact of pretransplant surgical procedures (SP) for pulmonary lesions of invasive fungal disease (IFD) on subsequent transplant outcome. We focused on the clinical outcomes of seven patients with pulmonary IFD who underwent segmentectomy (n = 4), lobectomy (n = 2) or abscess incision with drainage only (n = 1), and compared results to those of 21 patients carrying pulmonary IFD who never underwent invasive SP before allo-SCT. The rate of exacerbation of pulmonary lesions by 180 days after allo-SCT did not differ significantly between groups (32.2% vs 42.9%, P = 0.69). Moreover, no significant differences in non-relapse mortality (46.4% vs 42.3%, P = 0.93) or overall survival (53.6% vs 30.9%, P = 0.45) at 1 year were evident between groups. These results indicate that pretransplant SP for pulmonary lesions might have no survival benefit under the current antifungal prophylaxis or treatment modality.

[Portal vein thrombosis associated with idiopathic hypereosinophilic syndrome].

A 35-year-old man who previously underwent splenectomy for hereditary spherocytosis at age 29 visited our hospital complaining of fatigue that had started 7 days ago and right upper abdominal pain. Laboratory data showed increased white blood cell and eosinophil count accompanied by severe transaminitis and clotting abnormalities. Computed tomography scan showed multiple embolisms in the portal vein, superior mesenteric vein, right pulmonary artery, and inferior vena cava. Severe liver damage presumably caused by portal vein thrombosis was also observed. Anticoagulant therapies consisting of continuous arterial infusion of urokinase from the superior mesenteric artery and an intravenous infusion of recombinant human thrombomodulin and heparin dissolved the systemic thrombosis. Concurrently administered prednisone decreased the eosinophil count. With regard to eosinophilia, we were unable to find any connective tissue diseases, antibodies to parasites, or genetic anomalies including PDGFRA, PDGFRB, and FGFR1. Hence we diagnosed the patient with idiopathic hypereosinophilic syndrome (HES). Although thromboembolisms in patients with HES have been reported, the literature on portal vein thrombosis associated with HES is scarce. In the present case, the previous splenectomy may have contributed to the portal vein thrombosis.

[Definitive Radiotherapy for Esophageal Squamous Cell Carcinoma after Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning of Total Body Irradiation].

A 24-year-old man with acute lymphoblasticleukemia underwent allogeneicperipheral blood stem cell transplantation (allo-PBSCT)from a human leukocyte antigen-matched sibling after myeloablative conditioning, with a regimen including total body irradiation(TBI)(12 Gy/6 fractions), 6 years ago. The patient developed extensive chronic graft-versus-host disease(cGVHD)of the skin, mouth, liver, and gut four months after allo-PBSCT. Treatment with cyclosporine and prednisolone was necessary to control the cGVHD. Six years after allo-PBSCT, the patient experienced odynophagia and was diagnosed with cervical esophageal squamous cell carcinoma(cT1bN1M0, cStage II B). Because we considered laryngeal preservation, risk of anastomotic leakage, and infection related to the operation, the patient was planned to receive chemoradio- therapy with 5-fluorouracil and cisplatin. Regarding irradiation, the patient received radiotherapy(50.4 Gy/28 fractions)for a primary tumor and lymph node without an elective nodal area. The patient achieved complete response and remained disease- free without any treatment-related complications for 3 years.

Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Stenotrophomonas maltophilia (S. maltophilia) bacteremia causes significant morbidity and mortality in immunocompromised hosts. However, incidence and risk factors for mortality in S. maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain controversial. The primary aim of this study is to clarify factors associated with poor prognosis of allo-HSCT recipients with S. maltophilia bacteremia. METHODS: From January 2005 to December 2014, patients with hematological diseases and S. maltophilia bacteremia at a single transplantation center in Japan were examined for incidence and 90-day mortality. Prognostic factors associated with 90-day mortality among allo-HSCT recipients were analyzed by log-rank test, and significant variables in the univariate analysis were included in the multivariate Cox proportional-hazards regression model. RESULTS: A total of 65 patients, including 47 patients undergoing allo-HSCT, developed S. maltophilia bacteremia. The incidence of S. maltophilia bacteremia was significantly higher in allo-HSCT recipients compared to patients not receiving allo-HSCT (6.53 vs. 0.36 per 100 admissions, respectively; p < 0.01). The overall 90-day mortality in allo-HSCT recipients was 43%. Independent risk factors for 90-day mortality were low serum albumin (<3.0 g/dl) (HR = 10.86; 95% CI, 3.27-36.12) and high serum C-reactive protein (CRP) (≥10.0 mg/dl) (HR = 3.28; 95% CI, 1.00-10.72). Among 9 patients with both high CRP and low albumin, 5 had pneumonia at the onset of bacteremia and the remaining 4 patients developed pneumonia in a median of 3 days (range, 1 to 8 days) even under effective treatment. All 9 patients eventually died in a median of 2 days (range, 2 to 32 days). The probabilities of developing pneumonia in patients with or without high CRP and low albumin levels were 100% (9/9) and 10.5% (4/38), respectively (p < 0.01). CONCLUSIONS: Allo-HSCT recipients had higher rates of S. maltophilia bacteremia than did patients not receiving allo-HSCT. High serum CRP and low serum albumin at the onset of bacteremia are predictive of disease progression to pneumonia and poor prognosis.

[Disseminated fusariosis in patients with acute leukemia: a retrospective analysis of three cases].

We report three cases of fusariosis that occurred during the treatment of acute leukemia, during the past 5 years at our institution. Case 1: A 70-year-old male with relapsed and refractory acute lymphoblastic leukemia (ALL) developed fever and multiple nodular lesions in both the lungs. Blood culture that was subsequently obtained revealed Fusarium species. Treatment with liposomal-amphotericin B (L-AMB) was ineffective, and the condition of the patient deteriorated rapidly leading to death. Case 2: A 28-year-old male with T-ALL developed echthyma gangrenosum (EG) ulcers on the scrotum during conditioning for transplantation. Antifungal therapy with L-AMB was ineffective, and later, itraconazole and micafungin (MCFG) were introduced. However, the engraftment was not achieved, and the patient died on day 27. Microbiological examination of EG samples collected on day 13 revealed infection by Fusarium species post mortem. Case 3: A 50-year-old male with blast crisis of chronic myeloid leukemia developed EG primarily on the trunk during chemotherapy. The patient died without any response to L-AMB and MCFG. A culture obtained from EG on day 19 yielded Fusarium species, post mortem. The prognosis of fusariosis is extremely poor. However, skin lesions such as EG may assist in the early diagnosis of the disseminated disease.

Chronic myeloid leukemia relapsing ten years after allogenic bone marrow transplantation.

A 58-year-old female was diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis (BC) in 2004. The patient received imatinib, which quickly induced molecular remission, and subsequently underwent bone marrow transplantation (BMT) from an unrelated human leukocyte antigen (HLA)-identical donor. The post-transplant clinical course was essentially uneventful. In 2014, ten years after the BMT, the patient was admitted to our hospital complaining of lymphadenopathy, and blasts were observed in peripheral blood. The patient was diagnosed as having a CML relapse in myeloid BC, with leukemic infiltration in lymph nodes, and was treated with dasatinib. Subsequently, pleural effusion developed and nilotinib was administered, which induced normal blood counts without blasts and partial cytogenetic remission, one month after administration. Six months after the relapse, this patient underwent a second BMT from an HLA-matched unrelated donor. Recent studies have demonstrated the cumulative incidence of CML relapse more than five years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to be higher than in acute myeloid leukemia. Although rare, the possibility of late relapse should be considered in patients diagnosed with CML after allo-HSCT.

Retrospective analysis of clinical outcomes of the patients with chronic myeloid leukemia who stopped administration of tyrosine kinase inhibitors: a single institution experience.

We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients.

[Chronic myelogenous leukemia initially presenting with multiple subcutaneous tumors due to extramedullary hematopoiesis].

A 53-year-old woman was admitted with right upper-extremity pain and multiple subcutaneous masses. Bone marrow aspirate showed hypercellular marrow with increased myeloid components at all stages of maturation. Cytogenetic analysis of the bone marrow revealed 100% Philadelphia chromosome positivity along with BCR/ABL gene rearrangement, as demonstrated by polymerase chain reaction (PCR). A diagnosis of chronic phase of chronic myeloid leukemia (CML) was therefore made. Biopsy of one of the subcutaneous masses showed proliferation of granulocytes in various stages of differentiation. There were also erythroid cells and megakaryocytes, without p53 and CD34-positive blasts. These results suggested that the subcutaneous masses had developed from extramedullary hematopoiesis, not blastomas. The patient was administered dasatinib (DA) 140 mg, combined with radiation therapy for pain and peripheral neuropathy from the right axial extramedullary tumor. The patient showed complete hematological remission and the subcutaneous masses had disappeared 1 month after starting administration of DA. Because the patient did not achieve a cytogenetic response, the tyrosine kinase inhibitor nilotinib was administered. She will undergo allogeneic stem cell transplantation in the near future. Extramedullary hematopoiesis in the early stages of CML is uncommon. Our case emphasizes the need to elucidate the pathogenesis of extramedullary hematopoiesis in the early stages of CML.

Donor cell leukemia with bone marrow necrosis.

A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.

Azacitidine and gemtuzumab ozogamicin as post-transplant maintenance therapy for high-risk hematologic malignancies.

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m2) was administered for 7 days, followed by GO (3 mg/m2) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies.

Allogeneic Hematopoietic Stem Cell Transplantation for Adult Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Second Complete Remission.

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n = 382) was significantly lower than that in first complete remission (n = 1375) (51.8% versus 68.1%; P < .001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P < .001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P < .001) and relapse (HR = 1.88; P < .001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR = 2.10, P < .001) and nonrelapse mortality (HR = 2.68; P < .001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P < .001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Retrospective comparison of hematopoietic stem cell transplantation following reduced-intensity conditioning with fludarabine/low-dose melphalan plus 4 Gy TBI versus fludarabine/ busulfan plus 4 Gy TBI.

Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27-72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease.