As of 2018, adult leukemia ranks the 5th among common cancers in Saudi Arabia in both genders with the incidence of 6.69 % and estimated mortality of 9.5% . In one retrospective analysis of AML morphology of 153 patients at a tertiary referral center in Saudi Arabia, M6 comprised 1% among the FAB subtypes classification. . in a more recent retrospective study of 91 adult patients diagnosed with AML at Tertiary center in Riyadh, between 2006 and 2013. M1 subtype predominated the subtypes of AML as per FAB classification. Secondary AML accounted for 23% of all patients, and the majority of cases of secondary AML are transformed from MDS [3,4]. Unfortunately, there is scarcity in data regarding the risk factors and occurrence of secondary malignancy among post autologous stem cell transplant for multiple myeloma patients in our Saudi population. The Increased risk of secondary primary malignancy has been well established with lenalidomide maintenance following high-dose melphalan. Ultimately, the mortality rate from MM is significantly higher than the mortality from secondary primary malignancies with lenalidomide which has a survival benefit . In almost 50% of the cases, AML-M6 occurs secondary to alkylating agents or occupational exposure to mutagenic agents. Other cases may develop as a blast crisis of myeloproliferative disease or evolve from myelodysplastic syndrome [6,7].
We report a case of a 50-year-old male patient diagnosed with IgG lambda Multiple Myeloma post autologous transplant in 2016 on maintenance lenalidomide who presented with pancytopenia attributed initially to B12 deficiency with poor response to replacements therapy. His history dates back to1997, 2004 when he had biopsy-proven plasmacytoma from S2 vertebra followed by the development of new lytic lesion at T8 vertebral level. The two of which treated with radiotherapy to the involved area. In both occasions, he had no evidence of bone marrow involvement. Patient referred to our facility in 2014, with chronic back pain. At that time his MRI studies revealed small well-demarcated contrast-enhanced intraosseous lytic lesions involving in the bodies of C6, L1, L2, and L4, the iliac side of the left sacroiliac joint and right-side of the sacrum. Biopsy of the right sacral lytic lesion showed fragments of soft tissue, which were extensively infiltrated by sheets of plasma cells with minimal intervening stroma. They were mature-appearing but slightly atypical and exhibited a moderate amount of cytoplasm and slightly hyperchromatic nuclei with occasional binucleated cells. The plasma cells were positive for CD38 and CD138, (Figure 1A-1C).
Figure 1 (A) Biopsy of Lytic lesion with fragments of soft tissue which were extensively infiltrated by sheets of plasma cells with minimal intervening stroma. (B) Plasma cells from the bone lytic lesion with positive stain for CD 38. (C) Plasma cells from the bone lytic lesion showing positive stain for CD 138
They had strong staining for Lambda light chain while they are almost completely negative for Kappa light chain. He had normocellular bone marrow with no morphological involvement of plasma cells. His protein electrophoresis showed persistent monoclonal gammopathy (IgG-lambda). M-spike is 10.7% of total protein, and 54.3% of beta globulins (=8.23 g/l). Kappa/Lambda FLC Ratio 3.99. Patient started on VCD based chemotherapy protocol. He achieved very good partial remission after six cycles which were followed by melphalan based conditioning regimen and autologous stem cell transplant in 2016. He was then kept in lenalidomide maintenance therapy till the date of his admission in 2019 where he presented with two weeks history of increased lethargy, weakness and generalized fatigability following flu-like illness a month ago. His physical exam was remarkable for pallor but no jaundice. He had no organomegaly or palpable lymphadenopathy. His laboratory investigation revealed pancytopenia WBC 0.72 x10(9)/L , ANC 150 ,HB 2.9 g/dl ,MCV 87.1 fL; PLT 1 x 10(9)/L RETICS 0.5 ,Copper level of 11 µmol/l, Negative for Parvovirus B19 by PCR . Low B12 levels 80 pmol/l , Folate 31.24 ,TSH 0.62 and FT4 14.9 . Peripheral blood morphology showed marked pancytopenia, few neutrophils with toxic changes and rare dysplastic nucleated red blood cells. Total protein 55, Albumin 26.6, Ig Free light chain, Lambda 82.2, Kappa Lambda FLC ratio 1, No monoclonal protein band detected with normal immunofixation. Patient’s counts did not recover despite the withdrawal of lenalidomide and adequate replacements with vitamin B12 injections. He continued to require support with blood and its products. He had dry Bone marrow tap; thus, flow cytometry could not be performed. His trephine biopsy showed significant erythroid hyperplasia with immature looking cells, and abnormal cells infiltrate (Figure 2A-2D). A 2nd opinion obtained from the mayo clinic. That reported Markedly hypercellular bone marrow, 90% of which are Erythroid precursors. It had Left-shifted morphology with megaloblastic changes. Abundant pronormoblasts comprise approximately 90% of the bone marrow cellularity. Myeloid precursors: Markedly decreased quantity, normal morphology, blasts not increased. Megakaryocytes: Normal quantity, atypical morphology with increased small, hypolobated forms. Lymphocytes: No cytological atypia, no abnormal lymphoid aggregates. Plasma cells: Quantity is borderline increased (5%).
Figure 2: (A) Dilute bone marrow aspirate. (B) Trephine bone marrow showing marked hypercellularity. (C)and((D) showing the significant erythroid hyperplasia with abundant pronormoblasts
The immunohistochemistry of pronormoblasts showed dim CD117 expression. CD34 showed no increase in blasts and highlights increased vessels. CD38, CD138, CD79a highlight borderline increased plasma cells (approximately 5%). The plasma cells stain polytypic for kappa and lambda immunoglobulin. Factor 8 highlights a spectrum of megakaryocytes. MPO and CD15 highlight markedly decreased granulocytes. CD20 and PAX5 highlight rare scattered B-cells. CD3 and CD5 highlight normally scattered T-cells. CD10 and CD30 are negative. Immunohistochemistry, bone marrow biopsy (block 1-A), performed at Mayo Clinic in Rochester, MN, antibodies to CD13, CD33, CD34, CD61, CD71, CD117, E-cadherin, Glycophorin A, Hemoglobin A, lysozyme, MPO, TdT, Parvovirus B19: Abundant large aggregates of pronormoblasts, positive for CD71, E-cadherin, CD117, glycophorin A (partial), and Hemoglobin A (partial weak), and are negative for CD13, CD33, CD34, lysozyme, MPO, and TdT. CD61 highlights adequate megakaryocytes with increased small, monolobated forms. Parvovirus B19 staining was negative (Figure 3A-3E).
Figure 3: Trephine bone marrow biopsy showing negative stain for (A) CD38, (B) CD 138. Positive stain for (C) CD 71, (D) E-cadherin and (E) Glycophorin A
Final Diagnosis of pure erythroid leukemia was made. The patient received induction chemotherapy with 7+3 protocol which was complicated with persistent pancytopenia and recurrent infections mainly with stenotrophomonas maltophilia pneumonia and bacteremia required prolonged intubation and ICU admission. His peripheral counts did not show any signs of recovery in spite of G-CSF support. And his follow up bone marrow biopsy reported hypocellular marrow, markedly reduced normal hematopoiesis (Figure 4). Of note, there was a small cluster of immature cells which was explained by administration of GCSF as it had negative immunohistochemistry stain for any residual disease.
Figure 4: Follow up bone marrow that showed hypocellular marrow and negative MRD
Unfortunately, the patient developed refractory septic shock and hemorrhagic cystitis with platelet refractoriness. His condition continued to deteriorate despite the maximal antibiotic, hematological and inotropic support and passed away on day 63 post induction.
Pure erythroid leukemia is a rare and diagnostically challenging entity. In accordance with 2016 WHO PEL is defined as an expansion of maturation‐arrested erythroblasts comprising at least 80% of nucleated cells in the bone marrow, ≥30% of which are proerythroblasts. It varies from erythroleukemia by the absence of myeloblast component and the presence of erythroid maturation is arrested. Nonetheless, the majority of PEL evolves from prior MDS. It has an aggressive course. Treatment options include induction chemotherapy or administration of hypomethylating agent with dim prognosis  . Plasma-blastic myeloma, metastatic malignancies to bone marrow and high-grade lymphoma can share similar morphology but the use of lineage‐specific markers is needed to guide the correct diagnosis .To the best of our knowledge, this is the first reportable case of acute pure erythroid-leukemia in multiple myeloma patient following autologous stem cell transplant. The differential diagnosis in this particular patient case included therapy-related MDS and AML, acute erythroid leukemia, relapsed multiple myeloma and megaloblastic anemia. Given our initial patient presentation with pancytopenia and low levels of vitamin b12, a course of a therapeutic trial of hydroxocobalamin started. However, with lack of hematological response in keeping with the patient history of received high dose melphalan as part of a conditioning regimen, the possibility of secondary malignancy raised.
There have been two reported cases in the literature before transplant era that linked melphalan use in MM patients with erythroleukemia. In 1976, Meytes, D et al. reported a case of 72-year-old Jewish female with Multiple myeloma who terminated into erythroleukemia following four years of cyclic therapy with melphalan (2-4 mg daily for one week, with two weeks off therapy) and prednisone . In 1987, Streuli, R., and W. Voellmy reported a case of a 74-year-old female with multiple myeloma who received melphalan for 19 months and developed erythroleukemia 23 months post initiation of treatment that displaced the myeloma cells entirely in the marrow . Nonetheless, our patient was kept in maintenance lenalidomide post-transplant which could have contributed to the development of therapy-related MDS which in turn transformed into AML. In one randomized control trial that randomized 614 patients with none progressive MM post autologous transplant and was younger than 65 years of age to either maintenance lenalidomide 10 mg per oral daily or placebo until relapse. Lenalidomide was associated with the occurrence of hematological cancers in 13 patients out of 306 in the lenalidomide group. Five of which had either AML or MDS . Despite the inconstancies, risk factors for secondary malignancies in multiple myeloma patients post autologous transplant have been identified in large single-institution series. They included exposure to Lenalidomide, age above 55, white non-Hispanic ethnicity, Low CD34+ cell dose, chemotherapy with alkylating chemotherapy and radiation exposure . While other study reported, 5-fold increased risk of MM in patients aged <65 years when compared to patients aged >75 years. Female gender predominated the cases of secondary malignancies. Nevertheless, the risk of secondary AML was also found to be significantly higher among Asian-Pacific Islanders . The latest IMWG consensus regarding secondary malignancies in multiple myeloma recommended performing a baseline bone marrow biopsy with cytogenetics to rule out evidence of an existing dysplasia or concerning cytogenetic aberrations in all patients prior the initiation of lenalidomide maintenance . In our patient, an allogeneic transplant from HLA matched sibling was considered as upfront following achieving remission and the process was initiated before induction chemotherapy, but unfortunately, our patient died from sepsis as a consequence of aplastic bone marrow despite the achievement of MRD negativity.
Our case report highlights the importance of taking into consideration acute pure erythroid leukemia into the differential diagnosis when encountering similar post autologous transplant patient with megaloblastic anemia that lacks response to appropriate replacement therapy and emphasizes the pivotal rule of immunophenotyping in diagnosis of this rare entity. Further collaborative research work from national transplant centers to determine risk factors and predictors of secondary hematological malignancies in post autologous transplant patients are needed.
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