Extramedullary Diseases Research Articles

The phase I clinical study of CART targeting BCMA with humanized alpaca-derived single-domain antibody as antigen recognition domain.

2535 Background: Several phase I clinical trials already shown Chimeric antigen receptor T cells (CART) targeting BCMA has the promised effects to treat the relapsed/refractory (RR) multiple myeloma (MM), RRMM. We developed CART cells (CART-BCMA) using one single-domain antibody as recognition domain. The anti-BCMA single-domain antibody was derived from the alpaca, and humanized with the affinity of 1.14nM. The CART-BCMA use the 4-1BB and CD3ζ intracellular regions as T cell activation domain. Methods: A phase I, single arm clinical study was conducted to assess safety and efficacy of CART-BCMA. The enrolled RRMM patients had received average 10 lines of prior treatment, no matter BCMA expression level on plasma cells. Patients were subjected to a lymphodepleting regimen with Cy (300-600 mg/m2, d-5, -4) and Flu (30 mg/m2, d-5 to d-3) before CART infusion at the dose of 2-10×106 CAR+ cells/kg. The efficacy was assessed based on the IMWG Criteria, and the toxicity was graded by CTCAE 4.02. Results: As of December 31, 2018, 16 patients were infused with autologous CART-BCMA cells, and had at least 1 month of follow-up. Many patients have M protein in serum, but haven't the high percent of plasma cells in bone marrow, which are difficult to be treated by CART cells because the tumor cells are aggregated, not diffused in bone marrow. 3 patiens were diagnosed with extramedullary diseases, were evaluated as PR at D28 (tumor SPD decreasing >50%). 13 patients haven't extramedullary diseases, at D28, ORR is 84.6% (11/13); At 10 weeks, 7 patients were evaluated, ORR is 100% (sCR/CR 42.8%, VGPR 14.3% , PR 42.8% ); 5 patients reached 16 weeks, 1 relapsed, 4 kept remission. The Pt3 and Pt6 shows the CRS grade 3 or 4, other patients shows the grade 0-2 CRS, the CRS is manageable. Conclusions: Our result demonstrates the promising efficacy compared with other reported results of CART targeting BCMA, and supports further development of this anti-RRMM cellular immunotherapy. Clinical trial information: NCT03661554.

Value of Peripheral Blood Cell Count and Its Ratio in Evaluating Prognosis of Newly Diagnosed Multiple Myeloma Patients with Non-bone-related Extramedullary Diseases

Value of Peripheral Blood Cell Count and Its Ratio in Evaluating Prognosis of Newly Diagnosed Multiple Myeloma Patients with Non-bone-related Extramedullary Diseases

Prognostic value of (18)F-FDG PET/CT in newly diagnosed multiple myeloma patients

Objective: To assess the prognostic value of (18)F-FDG PET/CT and its relationship with clinical features in newly diagnosed MM patients. Methods: A total of 123 patients with newly diagnosed MM in Tianjin Medical University Cancer Institute and Hospital from September 2008 to December 2017 were retrospectively reviewed. The overall survival (OS) and progression free survival (PFS) were estimated by Kaplan-Meier analysis and the distribution of OS and PFS were compared using log-rank test. Cox regression was used to identify the independent prognostic factors. Results: Of all 123 patients, there were 43 patients (35.0%) who had extramedullary diseases (EMD). Compared to the patients without EMD, the PFS (24.5 months vs 37.8 months, P<0.05) and OS (30.1 months vs 51.4 months, P<0.05) of the patients with EMD at diagnosed was significantly inferior. In multivariate analysis, β2-MG≥5.5 mg/L, age≥65, EMD on (18)F-FDG PET/CT and without CR at the ending of treatments were the four factors leading to poor prognosis. According to the above four factors, the patients were regrouped into low risk, medium risk and high risk groups, the significant difference existed (P<0.01) in these groups. Conclusion: (18)F-FDG PET/CT is helpful in predicting the prognosis of newly diagnosed MM patients.

Late-stage myeloma invades kidney without significant effect on renal function: findings from 53 autopsies in a single institute.

Renal manifestations of multiple myeloma (MM) including cast nephropathy, amyloidosis, and renal calcification have been widely recognized. However, the severity of histopathological findings has not been addressed so far, and the clinical significance of these pathological findings is unclear. We sought to clarify the relationship between the severity of renal pathology and clinical characteristics. We analyzed 53 autopsies performed on patients who died from MM. The kidneys were evaluated using light microscopy, and the severity of pathological findings was recorded. The most common renal lesion was cast nephropathy (n = 27). Other findings included amyloidosis (n = 10), renal calcification (n = 5), microbial infection (n = 4), and MM infiltration (n = 17). The incidence of MM infiltration was substantially higher than previously reported. Renal MM infiltration was detected even when bone marrow plasmacytosis was limited. However, a significantly higher degree of renal MM infiltration was observed when MM cells invaded the liver. No correlation was observed between serum creatinine levels and degree of MM infiltration, but these tended to be elevated when cast nephropathy was severe. These findings may provide clues to understand both renal injury and extramedullary diseases in patients with MM.

Prevalence and Clinicopathologic Significance of BRAF V600E Mutation in Chinese Multiple Myeloma Patients

BackgroundPrevious studies in Western countries demonstrated BRAF V600E mutation only in a small subset of multiple myeloma (MM) patients. However, the prevalence and clinicopathologic significances of this mutation remain unclear in Chinese MM patients. Patients and MethodsWe studied diagnostic bone marrow samples from 205 Chinese MM patients by allele-specific PCR to detect BRAF V600E mutation and by high-resolution melting assay to detect KRAS and NRAS mutations. The mutations were confirmed by independent assays. ResultsBRAF V600E mutation was found in 9.3% of the cases, the highest prevalence hitherto reported. In addition, the mutation was significantly associated with hypercalcemia and a male predominance but not with aggressive extramedullary diseases or a high serum creatinine level as reported in Western studies. Importantly, BRAF V600E mutation was an adverse prognostic factor for overall survival in younger MM patients by subgroup analysis. Concurrent analysis of RAS mutations highlighted differential alteration spectrum of RAS signaling between Chinese and Western MM, which may suggest a unique myeloma-related genetic profile in Chinese patients. ConclusionOur study revealed a higher prevalence of BRAF V600E mutation in Chinese MM patients. The associated prognostic impacts on younger patients could be beneficial to risk stratification and potential application of BRAF-targeted therapies in Chinese MM management. This is the first large-scale study revealing the prevalence and clinicopathologic significances of BRAF V600E mutation in Chinese myeloma.

Leukemic Pleural Effusion in Acute Promyelocytic Leukemia: A Case Report

In patients with acute myeloid leukemia (AML), pleural effusion may be attributed to various factors, including infection, hypoalbuminemia, and renal failure. However, leukemic infiltration of the pleural fluid is rarely reported and poorly understood. Extramedullary diseases have been reported with increasing frequency as the survival rates of patients with AML have increased. However, the reported prognostic effects of leukemic pleural effusion in patients with AML range from none to a worse prognosis. Here, we report a case of acute promyelocytic leukemia (APL) in a patient exhibiting leukemic pleural effusion with fluorescence in situ hybridization (FISH) results indicating the presence of the PML-RARA fusion gene. A 52-year-old man presented with pancytopenia, dyspnea, and fever. He had a medical history of hypertension, end-stage renal disease, and hepatitis B virus-related liver cirrhosis. A peripheral blood smear revealed the presence of multiple abnormally hypergranular promyelocytes. White blood cell differential counts were not performed due to severe pancytopenia. A bone marrow examination, immunophenotyping analysis, and cytogenetic and molecular studies revealed APL. The patient was treated with all-trans retinoic acid immediately after abnormal promyelocytes were observed in the peripheral blood smear, but induction chemotherapy was delayed because of his poor condition. His persistent dyspnea and abdominal discomfort led to a thoracentesis and the observation of abnormal promyelocytes that were positive for PML-RARA fusion gene by FISH. To our knowledge, this is the first report of leukemic pleural infiltration with PML-RARA fusion gene-positivity via FISH.

A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation

[Introduction] Many factors predicting the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) recipient have been reported so far and widely used to assess the potential risk of undergoing allogeneic HSCT. Residual disease is considered one of the risk factors in HSCT, and mainly evaluated by bone marrow aspiration before HSCT. However, disease statuses at the point of stem cell infusion potentially differ from that of pre-transplant evaluation depending on the sensitivity for conditioning therapy or proliferation speed of the blast. In this study, we assessed residual disease by bone marrow aspiration on the day of stem cell transplantation (called "day 0" of HSCT) in order to analyze the relationship between day 0 marrow statuses and HSCT outcomes.[Methods] This study was designed as a retrospective observational analysis, and we collected the patients who received first allogeneic HSCT for hematological malignant diseases between 2010 and 2014. Extramedullary diseases were excluded from the analysis. All HSCTs were consecutive and performed in our center. Bone marrow aspirated material was examined histopathologically, and residual blasts were evaluated by specific markers by immunostaining. If it has detected residual blasts even if only a few cells, it was defined non complete remission (CR) on day 0 (abbreviated as "non-day0CR"). We divided the patients into two groups according to the existence of residual blast in bone marrow on day 0 of HSCT.[Results] We analyzed 121 HSCT recipients including 35 with acute lymphoblastic leukemia, 3 with acute undifferentiated leukemia, 65 with acute myeloid leukemia, 17 with refractory anemia with excess blasts and 1 with blast phase of chronic myelogenous leukemia. The median follow-up of survivors was 983 days (range 330 - 2092 days), and overall survival (OS) was 72% (95% confidence interval: 63 - 79%) at 1 year after HSCT. In univariate analyses, age higher than median 44 year-old, non-CR at the time of pre-HSCT assessment, hematopoietic cell transplantation specific comorbidity index (HCT-CI) at least 1 point, reduced intensity conditioning, and non-day0CR were extracted as predictors of poor OS. With multivariate analysis, HCT-CI and day 0 marrow status were significantly associated with OS. Furthermore, when patients were limited to pre-transplant non-CR subgroup, the patients achieving complete malignancies-free state on day 0 showed comparable prognosis with those who maintained CR before conditioning (Figure 1). Relapse after allogeneic HSCT was observed in 31 patients, and cumulative incidence of relapse was 11% (95% confidence interval: 6 - 17%) at 1 year after HSCT. With univariate and multivariate analyses, there were significant differences between the patients with CR marrow and those with residual malignancies on day 0 (P = 0.002). There was no significant difference in non-relapse mortality between the two groups (P = 0.18).[Conclusions] We showed that bone marrow status on day 0 was significantly associated with OS and cumulative incidence of relapse. To our knowledge, this is the first report about the association with day 0 marrow status and post-HSCT prognosis. A malignancies-free state on day 0 could predict favorable prognosis in allogeneic HSCT, and the patient with residual malignancies on day 0 had lower OS and higher relapse rate. For the patients with residual malignancies on day 0, rapid tapering of immunosuppressant or arrangement of scheduled donor lymphocyte infusion may improve the outcomes. [Display omitted] DisclosuresMiyamura:Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria.

A Multicenter Phase I/Ib Study of Ipilimumab for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation

▪ BACKGROUNDThe prognosis for patients (pts) with hematologic malignancies (HM) who relapse after alloHSCT is dismal, and novel treatment options are urgently needed. Checkpoint blockade has the potential to augment the graft-vs-tumor (GVT) effect pharmacologically, but may increase the risk of graft-vs-host disease (GVHD). We conducted a multicenter, open-label phase I/Ib study of the CTLA4 blocking antibody ipilimumab in pts with relapsed HM after alloHSCT. METHODSThe primary objectives were to determine the MTD and evaluate safety. Secondary objectives were to assess efficacy and changes in circulating lymphocyte populations. Ipilimumab induction was given IV every 3 weeks for 4 cycles, followed by maintenance dosing every 12 weeks up to 1 year. Disease-specific response evaluations were performed at the mid-point (7 weeks), end of induction (13 weeks), and throughout maintenance. Immunophenotyping was assessed by 8-color flow cytometry. Two dose levels (3 mg/kg and 10 mg/kg) were studied in phase I. The 10 mg/kg dose was chosen for expansion on the basis of safety and efficacy results. RESULTSA total of 28 patients were enrolled. In phase I, 6 pts were treated at 3 mg/kg and 7 pts were treated at 10 mg/kg. In the phase Ib expansion cohort, 15 additional pts were treated at 10 mg/kg. Histologies included AML (n=12, including 3 pts with leukemia cutis), HL (n=7), NHL (n=4), and MDS (n=2), and 1 pt each had MM, MPN, and ALL. The median age at enrollment was 58 yrs. (range 22-75). The median number of prior therapies excluding transplant was 3 (range 2-11), and 19/27 (70%) of pts had received prior therapy for post transplant relapse. In the toxicity analysis, immune-related adverse events (irAEs) typical of ipilimumab were observed in 4 pts, including pneumonitis (n=1 gr2, n=2 gr4), diarrhea (n=2 gr 1), colitis (n=1 gr 3), and ITP (n=1 gr2). These irAEs were generally reversible with steroids, and 3 pts were able to resume ipilimumab. Five DLTs leading to discontinuation occured, including cGVHD (n=3, all liver, gr 3), aGVHD (n=1, gut, gr 2), and TRM (n=1) due to presumed sepsis in the context of gr4 pneumonitis and gr3 colitis. Seventeen pts discontinued due to progressive disease, and 6 pts remain on active treatment. In the efficacy analysis, none of the 5 evaluable pts treated at 3 mg/kg achieved a formal response by disease specific criteria. In the 21 evaluable patients treated at 10 mg/kg, 10 patients (48%) had disease reduction. The overall response rate (ORR) by formal disease specific criteria was 33%. Responders included a HL pt with a PR with dramatic reduction in widespread bony disease and a marrow CR by 7 weeks, and a MM pt with a highly refractory lung plasmacytoma who achieved a PR. Notably, 5/12 (42%) pts with AML achieved CR, including all 3 pts with leukemia cutis (see example in Fig. 1) and one pt with myeloid sarcoma. The responses in two of the three leukemia cutis pts were durable, with both pts still in CR at 6 and 8 months on study. With a median follow-up time among survivors of 8.5 mo., the 6 mo. OS is 67%. Immunophenotyping studies revealed that the absolute numbers of T cells (including CD3+, CD4+, CD8+, Tcon, and Treg) peaked at 4 weeks after initial dosing and trended back down by 8 weeks. The ratio of Treg/Tcon decreased between 24 to 41% in the 15 pts with samples available at each time point. In the 5 pts who achieved CR, the Treg/Tcon ratio was similar to the rest of the cohort at baseline (0.07 vs. 0.08, p=0.57), but by 8 weeks there was a trend toward a decreased ratio in CR pts (0.05 vs. 0.15, p=0.14). The absolute number of NK cells was lower in responders than in non-responders by the 8 week time point (p = 0.04). CONCLUSIONRepeated dosing of ipilimumab is feasible in pts with relapsed HM after alloHSCT, although at 10 mg/kg both irAEs and GVHD were observed on treatment. Ipilimumab in this setting can provide substantial anti-tumor activity in pts with both lymphoid and myeloid malignanices. Interestingly, chemorefractory extramedullary myeloid diseases such as leukemia cutis and myeloid sarcoma appeared to respond particularly well. The Treg/Tconv cell ratio decreased with treatment, consistent with enhancement of GVT. Checkpoint blockade is a promising new therapeutic approach for post alloHSCT relapse, and is worthy of exploration in future studies. [Display omitted] DisclosuresDavids:Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Other: ad board. Chen:Bayer: Consultancy, Research Funding. Armand:Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Infinity: Consultancy, Research Funding. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

PICALM–MLLT10 acute myeloid leukemia: A French cohort of 18 patients

The PICALM–MLLT10 fusion gene, generated by the t(10;11)(p12-13;q14-21) translocation, is a rare but recurrent event in acute leukemias. In this study, we assessed the characteristics and outcome of 18 PICALM–MLLT10 AML patients. As compared with non PICALM–MLLT10 patients (n=72), PICALM–MLLT10 AML were characterized by more frequent extramedullary diseases, CD7 expression and higher platelet counts. Three out of four therapy-related PICALM–MLLT10 AMLs had been previously treated for diffuse large B-cell lymphoma. The complete response rate was 71% after intensive chemotherapy. PICALM–MLLT10 patients had a shorter median overall survival than patients with favorable cytogenetics (12months vs. not reached, p=0.07) but not significantly different from those of intermediate (26months, p=0.32) or unfavorable cytogenetic groups (8months, p=0.13). Long term responses were achieved in a subset of patients after allogeneic stem-cell transplantation but also after high-dose cytarabine.

Acute leukemia presenting with extramedullary diseases and completely normal hemogram: An extremely unusual manifestation unique to pre‐B ALL

Acute lymphoblastic leukemia (ALL) is a clonal hematological disease characterized by inadequate normal hematopoiesis secondary to excessive proliferation of leukemic blasts and their impaired differentiation. As a result, patients usually manifest symptoms related to bone marrow failure. It's very uncommon for ALL patients to present with normal hemogram. Herein, we describe two patients who presented with excruciating bone pain at orthopedic clinics. Osteopathy involving multiple bones was noted initially, but acute leukemia was never considered as one of the differential diagnoses because of the completely normal hemogram in both cases. Consequently, the diagnosis of leukemia was slightly delayed. Upon literature review, we found that ALL patients with solely extramedullary diseases and nearly normal hemogram had exclusively pre-B disease. We also propose a putative hypothesis for this interesting finding.

Allogeneic Transplantation for Acute Myeloid Leukemia (AML) M2 with Translocation (8;21) and CD56 Positivity Is Effective Even for Patients with Relapsed Disease.

Background:Patients with AML-M2 with t (8;21) generally have a good prognosis. However, the subset who have CD56 expression on their leukemic cells have poor prognosis, with frequent extramedullary involvement, short initial remissions, and high mortality. To date, little is known about the outcomes after allogeneic transplantation for patients with these unique characteristics.Methods:The Loyola transplant registry was searched for patients who underwent allogeneic transplantation at Loyola University Chicago Medical Center, Illinois during the period between June, 1998 and May, 2004 with these features. Patients were included in the analysis if their bone marrow examination at presentation met the FAB criteria for AML-M2; t (8;21) (q22;q22) was present by conventional karyotyping or by fluorescence in-situ hybridization (FISH); and CD56 expression was demonstrated by flow cytometric analysis of the leukemic blasts.Results:Five patients were identified; median age was 40 years (range 26–57 years); three were male. Median time from diagnosis until transplant was 12 months (range 3–93 months). Two patients had extramedullary diseases manifested by paraspinal and orbital granulocytic sarcoma at presentation or at relapse. One patient had 9q- in addition to the t (8;21). Patients had received a median of three prior therapy regimens (range 1–10) before transplant, including one patient who underwent high-dose chemotherapy and autologous stem cell transplant. Despite this, 4/5 patients had relapsed or refractory disease at transplant. Preparative regimens were total body irradiation 12Gy plus cyclophosphamide 120mg/kg in four patients and IV busulfan 14mg/kg plus cyclophosphamide 120 mg/kg in one; graft versus host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Three patients received grafts from matched unrelated donors; the rest from siblings. Three patients received bone marrow ranging from 2.0–4.4 x108/kg WBC and two received peripheral stem cells 4.0–6.07 x106/kg CD34+. The median time to neutrophil engraftment (the first of three consecutive days with absolute neutrophil count above 500/ml) was 14 days (range 12–17). The median time to platelet engraftment (the first of seven days with platelet count above 20,000/ml without transfusion) was 15 days (range 11–29). At day 100, all assessable patients (N=4) were in remission by bone marrow morphology with undetectable t (8;21) by FISH. As of August 2004, three patients survive at a median follow-up of 21 months (range 2–74 months); all remain in complete remission. Grade IV GVHD of skin occurred in one patient and grade II GI GVHD occurred in two. One patient, who received ten chemotherapy regimens over a 93-month period before transplant, died from pneumonia and venoocclusive disease of the liver; the other died from aspergillosis.Conclusions:Long-term disease free survival is possible with allogeneic transplant among patients with AML-M2 with t (8;21) and CD56 expression despite relapsed or refractory diseases. Clinicians should consider allografts, even from unrelated donors, early in the course of the disease to avoid the likely relapses after conventional therapy and to reduce the morbidity and mortality often seen in heavily pre-treated patients.

Extramedullary Diseases as Presenting Features of Aleukemic Acute Monocytic Leukemia

Extramedullary Diseases as Presenting Features of Aleukemic Acute Monocytic Leukemia