ALBERT

Description: Background: Currently the main potential treatment for chronic myeloid leukemia (CML) blast phase (BP) are tyrosine kinase inhibitors. The aim of our study is to try to find any therapy in TKI resistant patients in CML BP. Material and methods: The patients were 5 male and one female (age range from 28 to 45 years old). 4 patients progressed to BP from chronic phase (CP), there was rapid progression from AP in other two pts (4 lymphoid, 1 myeloid, 1 undifferentiated). The pts were unresponsible to one or two second generation TKI treatment in BP (dasatinid, nilotinib). Two patients were also failed to respond to high dose cytarabine and methotrexate treatment after TKI failure. Chemotherapy «FLAG» (fludarabine, cytarabine high dose, G-CSF) was used to induce of CP. Results: Five of six pts achieved the second CP and deep response (1- CcyR, 3- MMR, and one BCR/ABL reduction to 0,371%).Two of these pts obtained deep response (CCyR, and bcr/abl reduction to 0.371% after unsuccessful treatment with dose mono cytarabine and methotrexat treatment. The response was short, the longest MMR duration is 48 days (patient is being prepared for ASCT). Conclusion: FLAG can induce deep molecular responses in BP pts resistant to TKIs. This regimen seems to be more effective than HDAC and HD MTX. The response is of short duration. Thus, in case of absence of relative sibling, haploidentical ASCT with unmanipulated bone marrow and posttransplantation cyclophosphamide could be the optimal treatment choice. The protocol for FLAG induced remission followed haploidentical ASCT is prepared. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4825 Wilms' tumor gene 1 (WT1) that encodes a transcription factor has elevated expression in 90% of AML. High level of WT1 gene expression in bone marrow and peripheral blood of patients with AML indicates the presence of leukemia tumor burden. Thus, quantifying assessment of the level of WT1 could predict relapse. It is important to monitor a universal marker in the absence of target molecular genetic abnormalities in the disease onset. There are few data related to extramedullary relapses. Here we describe the patient with extramedullary relapse without concomitant elevation of WT1 expression. The patient is 22 year old male with the first early bone marrow and CNS relapse of AML. Cytogenetics- (45XY, t (3, 5) (q29; q15), −7, der (7), add (11) (p15)). Blast cells immunophenotype was CD45 + CD34 + CD38 + CD117 +. There was high blast count with high expression of WT1 level (Tabl 1). And there was no expression of other molecular genetic prognostic markers. Therapy with high dose of cytarabine with intrathecal administration of cytotoxic drugs was conducted. The complete hematological and cytogenetic remission was achieved after the first induction. Also there was no any blast cell in the CSF, WT1 expression decreased by 1,87 log (WT1 level became normal). Consolidation of remission with three similar courses with high doses of cytarabine was conducted. Extramedullary relapse during bone marrow and CNS remission with unilateral lesion of the lacrimal gland and the periorbital area( 2.8 × 3.4×4.6 cm )was diagnosed in 6 month. Relapse was confirmed by histological and immunochemical study of the left lacrimal gland biopsy, blasts phenotype was similar to the phenotype of bone marrow blasts at AML onset. WT1 level in bone marrow and peripheral blood remained within normal limits: 15.5 WT1/104 ABL copies and 13.4 WT1/104 ABL copies respectively. Therapy with high dose cytarabine and mitoxantrone was used as an induction. After this therapy a local remission was diagnosed according to MRI. Consolidation courses were followed by a course of radiotherapy to the area of the left orbit. Bone marrow remission and low-level expression of WT1 remained to be normal. Thereafter the patient has undergone unrelated allogeneic bone marrow transplantation. Conclusion. We have described isolated AML relapse without elevation of WT1. A possible reason for normal level of expression of WT1 in patients with extramedullary relapse may be a small amount of the extramedullary formation, its location and features of blood supply of the body area. Disclosures: No relevant conflicts of interest to declare.

Description: Objectives: To the best of our knowledge, data from Gemtuzumab ozogamicin in Acute Myeloid Leukemia (AML) patients with failure of organ functions and poor performance status are extremely lacking. Moreover, the fast recovery from organ failure, after Gemtuzumab ozogamicin administration, has never been reported. This study aimed to demonstrate the efficacy and rapid response of Gemtuzumab ozogamicin in refractory acute myeloid leukemia (AML) patients with pulmonary and kidney failure and poor performance status. Three refractory AML patients, with organ dysfunction, are described. One patient was pre-treated with intensive chemotherapy, and two other patients progressed during Azacitidine treatment. Two patients had respiratory failure grade 2 and one patient suffered from acute kidney insufficiency. Two patients were highly febrile with an elevated С-Reactive Protein (CRP) level. The WHO performance status of three was measured in all patients. Gemtuzumab ozogamicin administration was performed in three patients, followed by a further switch to Gemtuzumab ozogamicin + Azacitidine or “7+3” treatment. Results: Gemtuzumab ozogamicin administration resulted in abrupt fever cessation in two febrile patients simultaneously with a rapid decrease in CRP level and fast resolution of respiratory failure. Recovery of kidney function was noticed rapidly in patients with renal insufficiency. The WHO performance status was elevated in all three patients. No adverse grade II–III effects were noticed. Further treatment made two patients eligible for intensive chemotherapy, one patient underwent allogeneic stem cell transplantation, and the patient with kidney failure obtained complete remission. Conclusions: Gemtuzumab ozogamicin therapy appeared to be safe and highly efficacious in relapsed/refractory AML patients with organ dysfunction, like pulmonary or renal failure and poor performance status, and may contribute to rapid recovery from organ failures.

Description: Dramatic changes in overall survival of patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) have occurred since tyrosine kinase inhibitors (TKIs) were implemented in the treatment strategy. But there are still many issues in therapy of advanced phase disease, especially in blastic phase (BP). Allogeneic stem cell transplantation (alloSCT) is still the only curative option for CML BP, so all efforts should be focused on bringing pts to alloSCT. Thus optimal approach to obtain at least stable hematologic response before alloSCT is needed. Since 2008, 14 pts (4 more pts with isolated extramedullary BP were not included) with CML BP were admitted to our clinic. These were 8 males and 6 females with a median age of 44 years (range; 21-63) at the time of BP. The types of BP were: biphenotypic (n=1), undifferentiated (n=1), myeloid (n=8) and lymphoid (n=4). All pts except 2 (1 with BP and 1 with accelerated phase) were initially diagnosed as CP. Median time from diagnosis to BP was 37 months (range; 0-83). Before BP all pts except 2 were pretreated with imatinib and 6 of them, after failing imatinib, received one or more new TKIs. First line therapy in BP was monotherapy with new TKI (n=5) or chemotherapy (“7+3”, “RACOP”, low doses of Ara-C, “Hyper-CVAD”, “Dexa+VCR”) with or w/o TKI (n=9). Responses are specified in table 1. FLAG regimen was subsequently given to 5 pts as second or more line therapy after failure of previous monoTKI (n=1) or Rx + TKI (n=4). Median time from BP to FLAG was 3,5 months (range; 1,5-21). The best response to FLAG therapy was complete hematologic (n=1), complete cytogenetic with (n=1) or w/o (n=1) major molecular response. There were no responses in 2 cases. All responders maintain their response after median follow up (FU) of 2 months (range; 1,5-5). All patients treated with FLAG are alive (2 after alloSCT, 3 pending alloSCT). Only 1 ptn reached alloSCT w/o any Rx after monoTKI. AlloSCT was successful in 4/5. Median FU time for patients alive after alloSCT is 12 months (range; 3,5-25). For whole group after a median FU of 14 months, 7/14 (50%) pts are alive, including 4 pts after alloSCT. Estimated 3-year overall survival for all pts is 54% (fig. 1). Conclusion All CML BP patients treated with TKIs alone lost their response in a short time. Responses were much more durable in pts treated with Rx +/- TKIs. FLAG regimen was effective even in pts with failure to previous Rx+TKIs. The majority of pts after alloSCT are alive. Chemotherapy, including FLAG with concomitant or subsequent TKIs, had advantage over monoTKI both in overall and progression free survival in CML BP. Disclosures: Lomaia: Novartis: Honoraria, Travel grants Other; Bristol-Myers Squibb: Honoraria, Travel grants, Travel grants Other. Zaritskey:University of Heidelberg: Research Funding.

Description: Abstract 4812 Backgound: The Wilms' tumor gene 1 (WT1), which is over-expressed in more than 90% of AML, is a useful marker for monitoring MRD. Quantification of WT1 transcript level in peripheral blood (PB) and bone marrow (BM) at recovery from chemotherapy reliably discriminates patients at different risks of relapse. It is known that WT1 expression may be a marker of future relapse in 1 CR AML patients, after allogenic BMT and WT1 reduction also is a prognostic during induction of the first episode of AML. But there no evidence of WT1 reduction value in AML relapse. Patients and methods: In our prospective study were 10 patients with the first AML relapse and 2nd bone marrow complete remission were studied. High level of WT1 at relapse and achieving 2nd remission were the main inclusion criteria. Median WT1 level at relapse was 4302,2 (range 540–13184) copies WT1/104 Abl. Monitoring of WT1 level were estimated in patients with median age 36,6 (range from 20 to 64). Median time from the first CR to the relapse was 16,47 months (range from 3 to 51 mo), so there were 6 patients with early relapse and 4 patients with late relapse respectively. Chemotherapy with high dose cytarabine (HiDAC, FLAG) used for 2nd CR induction. Results: Only 66,7% (6 patients) demonstrated WT1 normalization. All of patients (n=4) with high WT1 expression in bone marrow remission developed second relapse in a few months, median time to relapse was 4,45 months (range from 2,8 to 7,4 mo). While patients with normal WT1 level in 2nd remission had relapse free survival 83.3% at 20 months (p=0.048, Fisher exact test, two tailed). Only one of 6 patients developed an extramedullary relapse in 6 months. The groups of patients were comparable to cytogenetic and molecular risks. Conclusion: We have shown that high WT1 level in 2nd remission is predictive for early relapse. Thus, high WT1 level in 2nd remission is an indication for very early stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: BCR-ABL1-positive acute myeloid leukemia (AML) is a rare subtype of acute leukemia and can co-occur with different aberrations such as CBFβ-MYH11, RUNX1-RUNX1T1, PML-RARα, and NPM1. Based on leukemogenesis model, BCR-ABL belongs to the class I mutations, providing a proliferative advantage to the affected cells, where inv(16) is a characteristic class II event, conferring inhibition of differentiation and apoptosis. We observed BCR-ABL1-positive AML de novo without any other molecular/cytogenetic features and CBF-AML (inv(16) at relapse. There are no definite clinical management of BCR-ABL+ AML and it is still a debate whether BCR-ABL1-positive AML patients should be treated with TKI ± chemotherapy as the first-line therapy. A 61-year-old man was diagnosed as having AML in May 2018. Laboratory findings showed: 51.1x 109/L WBC with 58% of blast cells; 38.8% and 4% of blasts in bone marrow and in cerebrospinal fluid (CSF) respectively; but 50% t(9;22) positive cells by fluorescence in situ hybridization (FISH) and conventional cytogenetic analysis (CyG). Both qualitative and quantitative polymerase chain reaction (PCR) tests confirmed the presence of BCR-ABL1p190 (10.2%) without any ABL1 kinase domain mutations. No other molecular abnormalities including mutations FLT3/ITD, NPM1, MLL, JAK2/V617F, DNMT3A, IDH1/IDH2, ASXL1, EZH2 or fusion genes PML-RARα, CBFβ-MYH11, RUNX1-RUNX1T1, BCR-ABL1p210/p230 were found. Also, 5q-, 7q- or 20q deletions were not detected by FISH. Flow cytometry analysis demonstrated single population of leukemic cells with CD34+CD117+CD13+CD33+CD11c+/-CD4+/-MPO+immunophenotype. No organomegaly was revealed. There was no history of antecedent hematological disorder. The patient was diagnosed as BCR-ABL1+ AML with CNS disease. Undetectable MRD was achieved after 1st cycle of FLAG regimen with dasatinib and intrathecal chemotherapy (IC), which was stopped after 1 month because of severe liquor hypotension. There were no matched related/unrelated donor. Due to severe complications during induction chemotherapy (hemorrhoidal bleeding, paroxysmal atrial fibrillation, febrile neutropenia) he continued dasatinib monotherapy for the subsequent 4 months with stable uMRD. Therapy was interrupted for 1 month due to adverse events (grade 3 diarrhea, grade 3 peripheral edema). The relapse occurred in Nov 2018 (after 5 months of uMRD) with 20%, 11% and 3% of blasts in peripheral blood, in bone marrow and in CSF, respectively. Laboratory showed no BCR-ABL1 or t(9;22) by quantitative PCR (qPCR), FISH or CyG, but new transcript CBFβ-MYH11A was detected (100.2%) by qPCR. Cytogenetic analysis showed inv(16)(p13;q22) in 80% cells with absence of additional abnormalities. No mutations of FLT3/ITD,IKZF, TP53 were found. Noteworthy, the patient was refractory to induction chemotherapy "High dose cytarabine (Ara-C) + gemtuzumab ozogamicin (GO)" despite CBF-leukemia. CSF complete response was achieved after triple IC. Hematological remission was achieved after 2 cycles of "Ara-C with 5-azacitidine" in combination with tyrosine kinase inhibitors (TKI) - imatinib 800mg QD. Triple IC was continued once a month as a prophylaxis of CNS disease. After 6 cycles of therapy CBFβ-MYH11A demonstrated 2log reduction, BCR-ABL1 transcript remains undetectable. The patient is in stable hematological and CSF remission. The clone dynamic and treatment see in table 1. BCR-ABL1 positive AML remains a provisional entity inside a huge part of AML with unclear pathogenesis and clinical management. We presented the first description of BCR-ABL1+ AML de novo leukemia followed by CBF-leukemia at relapse, and a clearance of blast cells in preceding BCR-ABL1 positive cells. Despite the absence of leukemic BCR-ABL1 burden, probably its the subliminal expression is able to maintain the mutational background. While TKI treatment may allow to maintain BCR-ABL1+ AML uMRD, it did not prevent the relapse of AML. High dose combination chemotherapy with BCR-ABL inhibitors is advantageous in these leukemia types in patients ineligible for allogeneic hematopoietic stem cell transplantation. Disclosures Lomaia: Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. OffLabel Disclosure: Tyrosine kinase inhibitors of BCR-ABL (Dasatinib, Imatinib) were used in case of BCR-ABL positive AML in combination with chemotherapy

Description: Abstract 4286 AML M-4 with 〉30% bone marrow myeloblasts was detected in 63 y old woman 2 mo after a diagnosis of chronic myelomonocytic leukemia (CMMLgrade 2). Cytogenetics showed 46, XX, del(5)(q12 q14) (N=4)/46, XX (N=18). Immune-phenotyping showed CD34+ CD117+ CD13+ CD33+ CD38+ HLADR+ CD2+. Leukemia cells were negative for inv (16), BCR/ABL, NPM, TEL/AML1, MLL/AF4, PML/RARA and AML1/ETO. She was RBC-transfusion-dependent. Therapy with cytarabine and daunorubicin and later with FLAG was ineffective and bone marrow myeloblasts increased to 〉70% with severe granulocytopenia and infection including pulmonary aspergillosis. She then received lenalidomide, 10 mg/d for 21 d every 4 w Bone marrow myeloblasts decreased to about 20% and granulocytopenia resolved. RBC-transfusion–dependence decreased. Cytogenetic and FISH-testing showed no detectable cells with del(5). This has persisted for 5 mo. Disclosures: Off Label Use: Lenalidomide for the treatment of AML with 5q- deletion.

Description: Abstract 4345 Myeloid sarcoma (MS) is an extramedullary tumor composed of immature myeloid cells. Development of myeloid sarcoma may precede or accompany to AML, CML and other myeloproliferative diseases or myelodysplastic syndrome. About 95% of patients with isolated myeloid sarcoma develop AML within 1–48 months. Sites most commonly affected with myeloid sarcoma are bones, lymph nodes, skin and soft tissue. Isolated myeloid sarcoma of the breast is rare. There is no consensus on the choice of the optimal treatment strategy of primary extramedullary MS at the moment. However, there is evidence of the benefit of systemic chemotherapy, despite the localized nature of this disease. The patient is 30 years old female. The tumor of left breast 3.5 * 2.5 cm first time was identified in 07.2011. It was asymptomatic. Histological examination of the tumor revealed myeloid sarcoma (high expression of SD7, CD34, CD38, CD117, TDT, nucleophosmin, BCL-2, the heterogeneous expression of MPO and a low CD5 expression). MRI with contrast revealed 5 lesions of the left breast with different types of accumulation of contrast. According to CT scan of the thorax, abdomen, pelvis and MRI of the brain no other pathologic lesions have been identified. No abnormalities were also found during examination of peripheral blood and bone marrow. No expression of fusion genes, target gene mutations and abnormal expression of WT1 were revealed during molecular genetic examinations. Bone marrow cytogenetics was normal. The standard induction chemotherapy “7+3” regimen was conducted. 80% reduction of the left breast lesions (according to MRI, ultrasound) was achieved after the first treatment course. This course was followed by HDAC (1 cycle) and local radiotherapy (27 Gray) with complete clinical and radiological response according by PET. PET performed after therapy did not reveal metabolically active tissue in the breast. Second HDAC was used as a consolidation. According to the results of the control MRI remains a single fibrotic lesion in the left breast tissue, PET negative. At present, the patient clinically well for three months from the end of the last HiDAC. A complete remission continues for 7 months. We continue our observation In conclusion, myeloid sarcoma can occasionally involve the breast as an isolated mass in patients without a history or subsequent development of AML. Histologically, myeloid sarcoma can mimic a number of other neoplasms, but especially various types of lymphoma and breast carcinoma, and it can be easily misdiagnosed without an immunophenotypic workup. It remains to be determined whether chemoradiotherapy is superior to chemotherapy alone. In our case, we administered AML chemotherapy and incorporated local radiotherapy as well. Response assessment was performed by breast MRI and PET scans. Timely start of therapy and an adequate volume of therapy allow to achieve complete response in patients with myeloid sarcoma. Disclosures: No relevant conflicts of interest to declare.