B-cell Acute Lymphoblastic Leukemia (B-ALL) With Uncommon Symptoms

Presentation 

A 38-year-old male presented with a 4-month history of persistent lower back pain and intermittent arthralgias, initially attributed to mechanical causes and managed with analgesics. Over time, the pain became refractory, and he developed mild pygalgia and transient swelling of the right knee. There was no significant past medical history. Initial laboratory workup, including complete blood count and metabolic panel, was unremarkable. MRI of the lumbar spine revealed heterogeneous marrow signal changes without discrete mass or vertebral collapse. 

Despite symptomatic management, the patient developed progressive fatigue and new-onset hypercalcemia. Repeat laboratory evaluation revealed mild anemia and thrombocytopenia, but no circulating blasts. Given the constellation of persistent osteoarticular symptoms, hypercalcemia, and cytopenias, a hematologic malignancy was considered.^1-3 

Lab Values (Key Abnormalities)

Workup 

A bone marrow aspiration/biopsy revealed:

• >20% lymphoblasts
• Normocellular (30-40%) marrow with trilineage hematopoiesis
• Cytogenetic analysis revealed a complex karyotype with hypodiploidy and a novel t(7;12)(q22;p13) translocation and -9
• Flow cytometry confirmed B-cell lineage ALL
• No BCR-ABL1 rearrangement was detected^4,5

Diagnosis 

The patient was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL).^5,6 

Treatment

A systemic multiagent pediatric-regimen-inspired chemotherapy including an induction phase, intensification phase, consolidation, and maintenance was decided upon.

• Induction Phase: Vincristine, an anthracycline (e.g., daunorubicin or idarubicin), a corticosteroid (e.g., dexamethasone or prednisone) and pegasparaginase^6,7
• Intensification Phase: High-dose intravenous methotrexate and pegasparaginase^6,7
• Consolidation and Maintenance: Multiagent chemotherapy every 2-3 years, often with monthly vincristine, oral methotrexate, 6-mercaptopurine, and prednisone or dexamethasone^6,7
• Lumbar punctures with intrathecal (IT) cytarabine alternating with IT methotrexate⁶

Management  

During the induction and intensification phases of treatment in an adult with acute lymphoblastic leukemia (ALL), especially in the context of rare features such as osteoarticular symptoms, hypercalcemia, absence of peripheral blasts at diagnosis, and a novel cytogenetic abnormality, the following laboratory tests should be closely monitored to guide therapy, detect complications, and assess response:^5,6

• Frequent CBC and metabolic panels (twice weekly) for cytopenias and hypercalcemia management
• Tumor lysis markers (LDH, uric acid, phosphate) given high disease burden
• MRD assessment by flow cytometry/PCR at end of induction and intensification for risk stratification^8-10
• Cytogenetic monitoring for novel abnormality characterization^5,11,12

Discussion 

Risk stratification in adult ALL is primarily determined by cytogenetic and molecular features with clinical presentation playing a secondary role.^5,6,10 The presence of a complex karyotype (≥5 abnormalities), low hypodiploidy/near-triploidy, KMT2A rearrangements, and certain novel or rare translocations are all associated with high or very high risk, independent of other clinical factors.^11-13 The prognostic impact of these cytogenetic abnormalities is robust and persists even in the era of minimal residual disease (MRD) monitoring.^8-10 For example, complex karyotype and low hypodiploidy/near-triploidy confer a significantly increased risk of relapse and inferior overall survival, and are considered adverse risk features in multiple large cohort studies and clinical trials.^11-13 Conversely, high hyperdiploidy is associated with a more favorable prognosis.^11,12 

Novel cytogenetic abnormalities, such as uncharacterized translocations, should be interpreted with caution but are generally managed as high risk until further data are available, especially if they are accompanied by other adverse features (e.g., hypodiploidy, monosomy ⁷, or complex karyotype)^.5,11,12 The revised UKALL (United Kingdom ALL) genetic risk classification and other contemporary schemas now incorporate these findings, categorizing patients with complex karyotype, low hypodiploidy/near-triploidy, and JAK-STAT pathway abnormalities as very high risk, and those with KMT2A fusions as high risk.^5,6,12 

Rare clinical features such as hypercalcemia and osteoarticular involvement do not independently alter risk stratification but may correlate with aggressive disease biology or high-risk cytogenetic subtypes. ^1,2,14 The absence of peripheral blasts at diagnosis is not itself a risk factor but can contribute to diagnostic delay, which may impact outcomes if treatment is not promptly initiated^.3,5 

In summary, risk stratification for an adult with ALL presenting with rare clinical features and a novel cytogenetic abnormality should be based on the underlying cytogenetic and molecular findings, with complex karyotype, low hypodiploidy/near-triploidy, KMT2A rearrangements, and novel/rare translocations considered high or very high risk.^5,6,11-13 These patients require intensified therapy, close MRD monitoring, and early consideration of allogeneic hematopoietic stem cell transplantation in first remission.^6,8,9 Integration of clinical presentation and cytogenetic and molecular data is essential for comprehensive risk assessment and optimal management^.5,6,10 

Future Directions 

Future research should focus on characterizing novel cytogenetic abnormalities like the t(7;12)(q22;p13) translocation observed in this case, developing targeted therapies for high-risk cytogenetic subgroups, and optimizing MRD-guided treatment algorithms.^5,6,8,9 Additionally, investigating the molecular mechanisms underlying osteoarticular presentations and hypercalcemia in ALL may provide insights into disease biology and potential therapeutic targets.^1,2 

 References 

1. Slouma M, Hannech E, Ghedira H, et al. Osteoarticular manifestation of acute lymphoblastic leukemia in adults: a literature review. Clin Rheumatol. 2023;42(2):607-620. doi:10.1007/s10067-022-06459-7 
2. Trehan A, Cheetham T, Bailey S. Hypercalcemia in acute lymphoblastic leukemia: an overview. J Pediatr Hematol Oncol. 2009;31(6):424-427. doi:10.1097/MPH.0b013e3181a1c12b 
3. Li F, Wang J, Liu A, et al. Prolonged lumbosacral pain as the initial presentation in acute lymphoblastic leukemia in an adult: a case report. Medicine. 2019;98(24):e15912. doi:10.1097/MD.0000000000015912 
4. de Haas V, Ismaila N, Advani A, et al. Initial diagnostic work-up of acute leukemia: ASCO clinical practice guideline endorsement of the College of American Pathologists and American Society of Hematology guideline. J Clin Oncol. 2019;37(3):239-253. doi:10.1200/JCO.18.01468 
5. Gökbuget N, Boissel N, Chiaretti S, et al. Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel. Blood. 2024;143(19):1891-1902. doi:10.1182/blood.2023020794 
6. Gökbuget N, Boissel N, Chiaretti S, et al. Management of ALL in adults: 2024 ELN recommendations from a European expert panel. Blood. 2024;143(19):1903-1930. doi:10.1182/blood.2023023568 
7. Brown PA, Shah B, Advani A, et al. Acute lymphoblastic leukemia, version 2.2024, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2024;22(10):e246101. doi:10.6004/jnccn.2024.0059 
8. Theunissen P, Mejstrikova E, Sedek L, et al. Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood. 2017;129(3):347-357. doi:10.1182/blood-2016-07-726307 
9. Short NJ, Aldoss I, DeAngelo DJ, et al. Clinical use of measurable residual disease in adult ALL: recommendations from a panel of US experts. Blood Adv. 2025;9(6):1442-1451. doi:10.1182/bloodadvances.2024014387 
10. Beldjord K, Chevret S, Asnafi V, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014;123(24):3739-3749. doi:10.1182/blood-2014-01-547695 
11. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109(8):3189-3197. doi:10.1182/blood-2006-10-051912 
12. Moorman AV, Butler ER, Ward EJ, et al. Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study. Leukemia. 2022;36(3):625-636. doi:10.1038/s41375-021-01448-2 
13. Paulsson K, Johansson B. Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis. Blood. 2017;129(4):420-423. doi:10.1182/blood-2016-10-743765 
14. Khayyam N, Mansoor N, Maqsood S, Jabbar N. Hypercalcemia and disseminated osteolytic lesions with normal blood counts and absence of circulating blasts: a rare presentation of childhood B-lymphoblastic leukemia. J Pediatr Hematol Oncol. 2021;43(2):e301-e303. doi:10.1097/MPH.0000000000001822