scholarly journals Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Benoît Brethon ◽  
Elodie Lainey ◽  
Aurélie Caye-Eude ◽  
Audrey Grain ◽  
Odile Fenneteau ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Salvage Chemotherapy ◽  
Gemtuzumab Ozogamicin ◽  
Main Concern ◽  
Cell Transplant ◽  
Curative Intent ◽  
Hematopoietic Stem ◽  
Mixed Phenotype Acute Leukemia ◽  
Induction Failure ◽  
Mixed Phenotype

Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents’ agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.

A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia (SWOG 1312)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1634-1634 ◽  
Author(s):  
Anjali S. Advani ◽  
Anna Moseley ◽  
Michaela Liedtke ◽  
Margaret O'Donnell ◽  
Megan Othus ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Grade 3 ◽  
Mixed Phenotype

Abstract The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results. Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age > 18 years (yrs), > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) > Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any > Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4. Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. Disclosures Advani: Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.

Mixed Phenotype Acute Leukemia (MPAL) Has a High Frequency of Mutations in Epigenetic Regulatory Genes: Results from Whole Exome Sequencing

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3560-3560 ◽  
Author(s):  
Olive S. Eckstein ◽  
Linghua Wang ◽  
Jyotinder N. Punia ◽  
Steven M. Kornblau ◽  
Michael Andreef ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Acute Leukemia ◽  
Stem Cell Differentiation ◽  
Regulatory Genes ◽  
Exome Capture ◽  
Null Mouse ◽  
Hematopoietic Stem ◽  
Mixed Phenotype Acute Leukemia ◽  
Mixed Phenotype

Abstract Introduction: Mixed phenotype acute leukemia (MPAL) is a relatively rare and difficult to treat leukemia with features of at least two cell lineages (typically myeloid combined with B-ALL or T-ALL). Early abnormalities in hematopoiesis appear to result in specific types of bone marrow disorders and leukemias. Epigenetic changes, such as aberrant DNA methylation facilitated by mutated DNA methyltransferases, have been implicated in the pathogenesis of many hematopoietic disorders. A recent study of adult patients with T-ALL/myeloid mixed phenotype acute leukemia demonstrated a 50% mutation frequency in the DNMT3A gene (Kern et al., ASH 2012). Interestingly, a Dnmt3a-null mouse model in our lab develops both myeloid and lymphoid malignancies. We hypothesize that epigenetic genes are an important regulator of early stem cell differentiation and that mutations in these genes may cause abnormal stem cell differentiation resulting in the ambiguous phenomenon of mixed phenotype acute leukemia. Methods: We analyzed DNA from a total of 19 MPAL samples (12 T/myeloid, 6 B/myeloid, and 1 B-ALL/T-ALL), with an age range of 20-74 years old. Pathology and flow cytometry records were reviewed by a hematopathologist to ensure that all samples met WHO 2008 criteria for MPAL prior to analysis. Five of the samples were cytogenetically normal, 7 had complex karyotypes or other high risk features, 3 had intermediate risk cytogenetic abnormalities, 1 was Philadelphia chromosome positive, 2 had MLL rearrangement and 2 samples did not have cytogenetic data available. Exome capture array was performed with Nimblegen and sequencing runs were performed in paired-end mode using the Illumina HiSeq 2500 platform for next generation sequencing. Samples achieved >96% of the targeted exome bases covered to a depth of 20x or greater. Results were mapped to Human Reference Genome, common SNPs were eliminated and mutations were identified with variant allele frequency >0.05 (most were >0.2). Over 500 previously reported genes with mutations in leukemias and other cancers were assessed. Results: Twelve of the 19 samples (63%) had mutations in epigenetic regulatory genes. The most commonly mutated gene was DNMT3A with 6 patients (32%); 3 of these patients had T/myeloid subtype, 2 of these patients had B/myeloid subtype and 1 patient and B-ALL/T-ALL subtype. Other mutations in epigenetic regulatory genes were found in EZH2 (3 patients, 16%), IDH1 (2 patients, 11%), IDH2 (3 patients, 16%, all T/myeloid), TET1 (3 patients, 16%, all T/myeloid), and TET3 (3 patients, 16%). Interestingly, DNMT3A was co-mutated with TP53 in 5 patients, IDH2 in 3 patients, NRAS in 2 patients, TET3 in 1 patient, and NOTCH1 in 1 patient. Mutations were also frequently found in PRPF40B (6 patients, 32%), TP53 (5 patients, 26%), BRAF (4 patients, 21%), NOTCH1 (4 patients, 21%). Other genes found to be mutated at a lower frequency were RUNX1, GATA2, JAK2, KRAS, NRAS, SIRPA, LRP1B, and NF1. Conclusions: Identifying abnormalities in epigenetic regulators may provide additional understanding of the pathogenesis of these rare and difficult to treat disorders. Adults with AML and DNMT3A mutations have demonstrated worse clinical outcomes (Ley et al., 2010), suggesting that standard chemotherapy may not be sufficient to treat malignancies which arise from hematopoietic stem cells. This understanding may guide future decisions regarding the necessity of personalized genetic testing at the time of diagnosis, the appropriateness of stem cell transplantation as well as providing prognostic information and future therapeutic targets for these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Venetoclax and Decitabine for T/Myeloid Mixed-Phenotype Acute Leukemia Not Otherwise Specified (MPAL NOS)

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Heather Klocke ◽  
Zhao Ming Dong ◽  
Craig O’Brien ◽  
Nicholas Burwick ◽  
Robert E. Richard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Leukemia ◽  
Stem Cell Transplant ◽  
Treatment Guidelines ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Not Otherwise Specified ◽  
Mixed Phenotype Acute Leukemia ◽  
One Year ◽  
Mixed Phenotype

T/myeloid mixed-phenotype acute leukemia not otherwise specified (MPAL NOS) is an uncommon and aggressive leukemia without well-established treatment guidelines, particularly when relapsed. Venetoclax plus a hypomethylating agent offers a promising option in this situation since studies support its use in both acute myeloid and, albeit with fewer data to date, acute T-cell-lymphoblastic leukemias. We report the successful eradication of T/myeloid MPAL NOS relapsed after allogeneic stem cell transplant with venetoclax plus decitabine. A consolidative allogeneic stem cell transplant from a second donor was subsequently performed, and the patient remained without evidence of disease more than one year later. Further investigation is indicated to evaluate venetoclax combined with hypomethylating agents and/or other therapies for the management of T/myeloid MPAL NOS.

Allogeneic Hematopoietic Stem Cell Transplant with Ablative Conditioning Is Associated with Favorable Outcomes in Patients with Mixed Phenotype Acute Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3487-3487 ◽  
Author(s):  
Bartlomiej M Getta ◽  
Junting Zheng ◽  
Martin S. Tallman ◽  
Jae H. Park ◽  
Eytan M. Stein ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Mixed Phenotype Acute Leukemia ◽  
High Dose Cytarabine ◽  
Mixed Phenotype

Abstract Aim: To investigate outcomes of allogeneic hematopoietic stem cell transplant (allo-HCT) in patients with mixed phenotype acute leukemia (MPAL) and to describe genomic profile of MPAL. Methods: MPAL pts of all ages treated at out center (2002-2015) were included. Subtypes were classified based on the 2008 WHO Guidelines. Induction chemotherapy was categorized as ALL-type (N=10) defined by use ofasparaginase with corticosteroids (N=8) or hyper-CVAD (N=2) and AML-type defined by use of cytarabine andanthracycline withoutasparaginase, vincristine or steroids (N=33). Categorical variables were compared with Fishers exact test, overall survival (OS) and relapse free survival (RFS) with log-rank test/cox regression and cumulative incidence of relapse (CIR) with Greys test. Survivor curves were constructed with the Kaplan-Meier method. Results: 43 pts were identified, 29 (67%) underwent allo-HCT. Diagnostic disease features are presented in table 1. MPAL groups included B/Myeloid (N=16), T/Myeloid (N=14),Ph+/MPAL (Philadelphia chromosome, N=7), MLL/MPAL (11q23 translocation, N=5) and MPAL NOS (N=1). MLL/MPAL clustered in pediatric pts (17% v 8%) andPh+/MPAL in adults (20% v 11%). Median follow up for survivors (N=31) was 42.1 months (95% CI 20.5-68.4) and median OS was not reached (95% CI 28.1-NR). Cytogenetics wereavailable for 39 patients. 6 (15%) had a normal karyotype, 15 (38%) complex and 9 (23%) had a monosomal karyotype. The most common monosomywas -7 (n=6, 15%) and polysomywas +21 (N=5). Translocations were seen in 23 (59%) most commonly involving 14(q31-32) (N=5), This region was rearranged in cases of B or T/myeloid MPAL only. The region encodes several genes associated with B cell NHL (BCL11B, IGH) and T cell leukemia (TCL1A, TCL6). Molecular typing was available in 26 (60%) patients and 9/26 (35%) had targetable mutations (FLT3, NOTCH, IDH or RAS). Most frequently mutated genes included NOTCH (3/6) seen in B and T/Myeloid MPAL and FLT3-ITD seen mostly in T/Myeloid MPAL (4/10). Mutations in IDH1 or IDH2 were seen only in B/Myeloid MPAL and no pts harbored mutant NPM1. Mutant TET2 (N=5/14) and DNMT3A (N=3/15) were seen only in adults and may represent underlying clonal hematopoiesis. CR following first induction was achieved in 81% (35/43) with a similar rate in adult (21/25, 84%) and pediatric (14/18, 78%) pts. Similar high rates of CR were attained after ALL-type induction 8/10 (80%) and AML-type induction 27/33 (81%). In adults, CR was attained in 11/12 (92%) pts who received high dose cytarabine andmitoxantroneand in 5/7 (71%) with 7+3 (idarubicinordaunorubicin). In pediatric pts, CR was attained in 10/12 (83%) of those treated with DCTER and in 6/7 (86%) treated with a multi-agent pediatric ALLregimen. All pts withPh+/MPAL received induction chemotherapy (4 AML-type and 3 ALL-type) withimatinib(N=4) ordasatinib(N=3) and all achieved CR. All MLL/MPAL patients achieved CR after induction. The median follow-up for transplant survivors was 45 months (95% CI 17.0-82.8) and median OS was not reached (95% CI 15.4-NR). Most adults (23/25 versus 6/18 in pediatric cases) and pts withPh/MPAL (7/7) and MLL/MPAL (4/5) underwent allo-HCT. Remission status at transplant, conditioning intensity and GVHD prophylaxis regimens were not different amongst MPAL types undergoing transplant (table 1). Relapse and OS after transplant were similar for pediatric and adult pts, and those receiving T cell depleted and conventional grafts. MLL/MPAL (p=0.031) and use of reduced intensity conditioning (p<0.001) were associated with higher cumulative incidence of relapse (table 2). In pediatric patients transplant was not associated with a survival benefit (p=0.183), while a potential benefit could not be assessed in adults as most underwent HCT. Conclusion: MPAL is uncommon and lacks a standard treatment approach. Based on these data adults should receive induction chemotherapy with either high-dose cytarabine/mitoxantrone or 7+3 and undergo allo-HCT with ablative conditioning in CR1. The selection of pediatric patients who undergo allo-HCT is more complex due to the higher incidence of MLL/MPAL. MLL/MPAL may be associated with inferior transplant outcomes and should be a target for cellular and pharmacologic interventions following transplant. Extended genomic profiling in MPAL is recommended in all pts as 1/3 had potential targets for maintenance therapy following transplant. Disclosures Park: Baxalta: Consultancy; Amgen: Consultancy; Juno Therapeutics: Research Funding; Novartis: Consultancy. Stein:Novartis: Consultancy; Celgene: Other: Advisory Board, Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding. Roshal:BD Biosciences: Consultancy. Kernan:Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding.

How I treat mixed-phenotype acute leukemia

Blood ◽  
2015 ◽  
Vol 125 (16) ◽  
pp. 2477-2485 ◽  
Author(s):  
Ofir Wolach ◽  
Richard M. Stone
Keyword(s):  
Acute Leukemia ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Classification Systems ◽  
World Health ◽  
Lymphoid Tissues ◽  
Cell Transplant ◽  
Mixed Phenotype Acute Leukemia ◽  
Health Organization ◽  
Mixed Phenotype

Abstract Mixed-phenotype acute leukemia (MPAL) encompasses a heterogeneous group of rare leukemias in which assigning a single lineage of origin is not possible. A variety of different terms and classification systems have been used historically to describe this entity. MPAL is currently defined by a limited set of lineage-specific markers proposed in the 2008 World Health Organization monograph on classification of tumors of hematopoietic and lymphoid tissues. In adult patients, MPAL is characterized by relative therapeutic resistance that may be attributed in part to the high proportion of patients with adverse cytogenetic abnormalities. No prospective, controlled trials exist to guide therapy. The limited available data suggest that an “acute lymphoblastic leukemia–like” regimen followed by allogeneic stem-cell transplant may be advisable; addition of a tyrosine kinase inhibitor in patients with t(9;22) translocation is recommended. The role of immunophenotypic and genetic markers in guiding chemotherapy choice and postremission strategy, as well as the utility of targeted therapies in non–Ph-positive MPALs is unknown.

B-Cell/Mixed Phenotype Acute Leukemia Following Lenalidomide Maintenance For Multiple Myeloma: A Study Of Two Cases

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S153-S153
Author(s):  
F Fei ◽  
V Reddy ◽  
F Rosenblum
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Acute Leukemia ◽  
Hematologic Malignancies ◽  
Second Primary ◽  
Second Primary Malignancy ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Mixed Phenotype Acute Leukemia ◽  
Mixed Phenotype

Abstract Introduction/Objective The incidence of patients with multiple myeloma (MM) followed by hematologic malignancies as second primary malignancy is around 0.8 – 3.1%. The majority of cases are myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), however, acute lymphoblastic or mixed phenotype leukemia can be rarely observed. Methods A retrospective chart review was performed for patients diagnosed with acute lymphoblastic or mixed phenotype leukemia from January 2009 through February 2020. Two patients were identified and the corresponding clinical data were reviewed. Results Case 1 was a 74-year old male diagnosed with pre-B ALL 5 years after an IgG Lambda MM. His MM therapy included Bortezomib-based chemotherapy followed by Lenalidomide maintenance. Pre-B diagnosis was confirmed on a pelvic lesion biopsy with sheets of intermediate sized cells (CD45+, PAX5+, CD34+, CD43+, CD10+, BCL6+ and BCL2+). The patient had 4 cycles of HyperCVAD chemotherapy, followed by Blinatumomab and Inotuzumab treatment. Unfortunately, the patient was referred to hospice 2 years after the diagnosis of ALL. Case 2 was a 69-year old male diagnosed with mixed phenotype acute leukemia 8 years after an lgA Lambda MM with del 13q and Trisomy 11. The patient was treated with Bortezomib-based chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and Lenalidomide maintenance. Bone marrow biopsy showed around 79% blasts (CD34+, PAX-5+, CD79a+ and MPO+). Flow cytometry from bone marrow showed 90% precursor B cells, however MPO was negative. Furthermore, a DNTM3A p.T835M missense variant (25-30% fraction) was identified by next generation sequencing (NGS). The patient was scheduled for Hyper-CVAD chemotherapy. Conclusion Lenalidomide maintenance following auto-HSCT is considered a standard therapy for MM patients. Recent studies indicate that Lenalidomide maintenance is associated with an increased risk of second primary hematologic malignancies. Although AML and MDS are more commonly seen, ALL and rarely mixed phenotype leukemias can occur.

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